|
- Rev
Neurol. 2005 Oct 1-15;41(7):409-22.
[Autosomal recessive cerebellar ataxias. Their
classification,
genetic features and pathophysiology.]
[Article in Spanish]
Espinos-Armero C, Gonzalez-Cabo P, Palau-Martinez F.
Institut de Biomedicina de Valencia (CSIC), 46010
Valencia, Espana.
INTRODUCTION AND DEVELOPMENT. Autosomal recessive cerebellar
ataxias (ARCA) are a heterogeneous group of rare neurological
disorders involving both central and peripheral nervous system, and in
some case other systems and organs. They use to have early onset
before the age of 20. Based on pathogenic mechanisms five main types
may be distinguished: congenital (developmental disorder),
mitochondrial ataxias, ataxias associated with metabolic disorders,
ataxias with a DNA repair defect, and degenerative ataxia with unknown
pathogenesis. The most frequent in Caucasian population are Friedreich
ataxia and ataxia-telangiectasia. Other forms are much less common,
and include abetaliproteinemia, ataxia with vitamin E deficiency
(AVED), ataxia with oculomotor apraxia types 1 (AOA1) and 2 (AOA2),
early onset cerebellar ataxia with retained reflexes,
Charlevoix-Saguenay spastic ataxia, and Joubert syndrome. The
prevalence of ARCA has been estimated to 7 in 100,000 inhabitants.
These diseases are due to mutations in specific genes, some of which
and its encoded proteins have been identified, such as FRDA (frataxin)
in Friedreich ataxia, APTX (aprataxin) in AOA1, aTTP (a-tocopherol
transfer protein) in AVED, and STX (senataxin) in AOA2. Due to
autosomal recessive inheritance, previous familial history of affected
individuals unlikely. CONCLUSIONS. Most of these cerebellar ataxias
have no specific treatment with exception of the ataxia associated
with deficiency coenzyme Q10 and abetalipoproteinemia. Clinical
diagnosis must be confirmed by ancillary tests such as neuroimaging
(magnetic resonance, scanning), electrophysiological examination, and
mutation analysis when the causative gene has been identified. Correct
clinical and genetic diagnosis is important for appropriate prognosis
and genetic counseling and, in some instances, pharmacological
treatment.
- Clin
Neurophysiol. 2005 Oct 6; [Epub ahead of print]
Triple stimulation technique in patients with
spinocerebellar ataxia type 6.
Sakuma K, Adachi Y, Fukuda H, Kai T, Nakashima K.
Department of Biological Regulation, Section of
Environment and
Health Science, School of Health Sciences, Faculty of Medicine,
Tottori University, 86 Nishimachi, Yonago, Japan; Division of
Neurology, Institute of Neurological Sciences, Faculty of Medicine,
Tottori University, 36-1 Nishimachi, Yonago, Japan.
OBJECTIVE: To establish further evidence that SCA6
may not be a
pure cerebellar syndrome. METHODS: Seven patients with genetically
confirmed SCA6 and 9 age-matched normal controls were studied.
Recordings of the CMAP were obtained from the right first dorsal
interosseus muscle. Transcranial magnetic stimulation of the left
motor cortex was applied to the contralateral scalp with a plane
figure-of-8 coil. Conventional transcranial magnetic stimulation
(TMS), central motor conduction time (CMCT) by F-wave method and the
triple stimulation technique (TST) amplitude ratio (TST test/TST
control) were investigated. RESULTS: The mean resting motor threshold
and mean CMCT did not show significant differences between normal
controls and patients, but the mean TST amplitude ratio was
significantly smaller in patients than in controls. CONCLUSIONS: An
abnormal TST represents upper motor neuron loss, central axon lesions
or conduction blocks, or inexcitability in response to TMS. The lack
of pathological changes in the corticospinal tract of patients with
SCA6 indicates that this abnormality may be caused by crossed
cerebellar diaschisis, or a functional disorder in the brain resulting
from CACNA1A mutations. SIGNIFICANCE: TST is a useful method for
quantifying corticospinal tract dysfunction.
PMID: 16214408 [PubMed - as supplied by publisher]
- Neurology.
2005 Oct 11;65(7):1114-6. Related Articles, Links
Autoantibodies in postinfectious acute cerebellar
ataxia.
Uchibori A, Sakuta M, Kusunoki S, Chiba A.
Department of Neurology, School of Medicine, Kyorin
University,
Mitaka, Tokyo 181-8611, Japan.
The authors found serum
immunoglobulin M (IgM) autoantibody in a
patient with typical acute cerebellar ataxia (ACA) and identified the
antigen molecule as triosephosphate isomerase (TPI). TPI antigenicity
to the patient's antibody was the highest in the cerebellar tissue.
Eight of 23 patients with ACA had increased IgM anti-TPI antibody
titers vs those of healthy controls. Preceding Epstein-Barr virus
infection was confirmed serologically in all 8 patients. Anti-TPI
antibody decreased with clinical improvement.
PMID: 16217070 [PubMed - in process]
-
- Ann
Neurol. 2005 Sep 28; [Epub ahead of print]
New mutations in protein kinase Cgamma associated
with
spinocerebellar ataxia type 14.
Klebe S, Durr A, Rentschler A, Hahn-Barma V, Abele M,
Bouslam N,
Schols L, Jedynak P, Forlani S, Denis E, Dussert C, Agid Y, Bauer P,
Globas C, Wullner U, Brice A, Riess O, Stevanin G.
Institut National de la Sante et
de la Recherche Medicale U679
(formerly U289) and Institut Federatif de Recherche en Neurosciences,
Paris, France.
Autosomal
dominant cerebellar ataxias (ADCA) are a heterogeneous
group of neurological disorders. Point mutations in the gene encoding
protein kinase Cgamma (PRKCG) are responsible for spinocerebellar
ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a
large series of 284 ADCA index cases, mostly French (n=204) and German
(n=48), in whom CAG repeat expansions in the known SCA genes were
previously excluded. Six mutations were found that segregated with the
disease and were not detected on 560 control chromosomes, including
F643L (exon 18), already reported in another French kindred. Five new
missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10
(G360S) and 18 (V692G). All but one (V692G) were located in highly
conserved regions of the regulatory or catalytic domains of the
protein. All six SCA14 families were French and there was no evidence
of reduced penetrance. The phenotype consisted in a very slowly
progressive cerebellar ataxia with a mean age at onset of 33.5+/-14.2
years (range 15 to 60 years), occasionally associated with executive
dysfunction, myoclonus, myorythmia, tremor or decreased vibration
sense. SCA14 represented only 1.5% (7/454) of French ADCA families but
none of the German families. It should, however, be considered in
patients with slowly progressive ADCA, particularly when myoclonus and
cognitive impairment are present. Ann Neurol 2005.
PMID: 16193476 [PubMed - as supplied by publisher]
- Neurol
Sci. 2005 Sep 28; [Epub ahead of print]
Novel compound heterozygous mutations in
sacsin-related ataxia.
Yamamoto Y, Hiraoka K, Araki M, Nagano S, Shimazaki
H, Takiyama Y, Sakoda S.
Department of Neurology D4, Osaka University Graduate
School of
Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
High prevalence of a form of
autosomal recessive spastic ataxia
with early onset was originally described among French Canadians in
the Charlevoix-Saguenay region, in northeastern Quebec. Since the
responsible gene (SACS) was identified, mutations in the SACS gene
have been described in Tunisia, Italy, Turkey, and Japan. The mutation
sites found outside Quebec are different from the ones in Quebec. All
patients outside Quebec, except one Italian patient, have been
reported to have homozygous mutations. The authors report here
identical twin sisters with novel compound heterozygous mutations
(c.[2951_2952delAG]+[3922delT]) in the SACS gene.
PMID: 16198375 [PubMed - as supplied by publisher]
- Curr
Opin Clin Nutr Metab Care. 2005 Nov;8(6):641-6.
Clinical aspects of coenzyme Q10: an update.
Littarru GP, Tiano L.
Institute of Biochemistry, Polytechnic University of
Marche, Via
Ranieri, Ancona, Italy.
PURPOSE OF REVIEW: Coenzyme Q10 is administered for
an
ever-widening range of disorders, therefore it is timely to illustrate
the latest findings with special emphasis on areas in which this
therapeutic approach is completely new. These findings also give
further insight into the biochemical mechanisms underlying clinical
involvement of coenzyme Q10. RECENT FINDINGS: Cardiovascular
properties of coenzyme Q10 have been further addressed, namely
regarding myocardial protection during cardiac surgery, end-stage
heart failure, pediatric cardiomyopathy and in cardiopulmonary
resuscitation. The vascular aspects of coenzyme Q10 addressing the
important field of endothelial function are briefly examined. The
controversial issue of the statin/coenzyme Q10 relationship has been
investigated in preliminary studies in which the two substances were
administered simultaneously. Work on different neurological diseases,
involving mitochondrial dysfunction and oxidative stress, highlights
some of the neuroprotective mechanisms of coenzyme Q10. A 4-year
follow-up on 10 Friedreich's Ataxia patients treated with coenzyme Q10
and vitamin E showed a substantial improvement in cardiac and skeletal
muscle bioenergetics and heart function. Mitochondrial dysfunction
likely plays a role in the pathophysiology of migraine as well as
age-related macular degeneration and a therapy including coenzyme Q10
produced significant improvement. Finally, the effect of coenzyme Q10
was evaluated in the treatment of asthenozoospermia. SUMMARY: The
latest findings highlight the beneficial role of coenzyme Q10 as
coadjuvant in the treatment of syndromes, characterized by impaired
mitochondrial bioenergetics and increased oxidative stress, which have
a high social impact. Besides their clinical significance, these data
give further insight into the biochemical mechanisms of coenzyme Q10
activity.
PMID: 16205466 [PubMed - in process]
- Mov
Disord. 2005 Oct 6; [Epub ahead of print]
Spinocerebellar ataxia associated with a mutation in
the
fibroblast growth factor 14 gene (SCA27): A new phenotype.
Brusse E, de Koning I, Maat-Kievit A, Oostra BA,
Heutink P, van Swieten JC.
Department of Neurology, Erasmus MC University
Medical Center
Rotterdam, The Netherlands.
Autosomal dominant cerebellar ataxias (ADCAs) are
genetically
classified into spinocerebellar ataxias (SCAs). We describe 14
patients of a Dutch pedigree displaying a distinct SCA-phenotype
(SCA27) associated with a F145S mutation in the fibroblast growth
factor 14 (FGF14) gene on chromosome 13q34. The patients showed a
childhood-onset postural tremor and a slowly progressive ataxia
evolving from young adulthood. Dyskinesia was often present,
suggesting basal ganglia involvement, which was supported by
functional imaging in 1 patient. Magnetic resonance imaging (MRI) of
the brain showed only moderate cerebellar atrophy in the 2 eldest
patients. Neuropsychological testing indicated low IQ and deficits in
memory and executive functioning. Behavioral problems were also
observed. Further investigations will have to determine the role of
FGF14 in the pathogenesis of neurodegeneration and the frequency of
this FGF14 mutation in SCA. (c) 2005 Movement Disorder Society.
PMID: 16211615 [PubMed - as supplied by publisher]
--
- PLoS Genet. 2005 Sep;1(3):e41. Epub 2005 Sep 30.
Positive Selection of a
Pre-Expansion CAG Repeat of the Human SCA2 Gene.
Yu F, Sabeti PC, Hardenbol P, Fu Q, Fry B, Lu X,
Ghose S, Vega R,
Perez A, Pasternak S, Leal SM, Willis TD, Nelson DL, Belmont J, Gibbs
RA.
Human Genome Sequencing Center, Baylor College of
Medicine,
Houston, Texas, United States of America.
A region of approximately one megabase of human
Chromosome 12
shows extensive linkage disequilibrium in Utah residents with ancestry
from northern and western Europe. This strikingly large linkage
disequilibrium block was analyzed with statistical and experimental
methods to determine whether natural selection could be implicated in
shaping the current genome structure. Extended Haplotype Homozygosity
and Relative Extended Haplotype Homozygosity analyses on this region
mapped a core region of the strongest conserved haplotype to the exon
1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA
sequencing of this region of the SCA2 gene revealed a significant
association between a pre-expanded allele
[(CAG)(8)CAA(CAG)(4)CAA(CAG)(8)] of CAG repeats within exon 1 and the
selected haplotype of the SCA2 gene. A significantly negative Tajima's
D value (-2.20, p < 0.01) on this site consistently suggested
selection on the CAG repeat. This region was also investigated in the
three other populations, none of which showed signs of selection.
These results suggest that a recent positive selection of the
pre-expansion SCA2 CAG repeat has occurred in Utah residents with
European ancestry.
PMID: 16205789 [PubMed - in process]
- Human
Molecular Genetics Advance Access originally published online
on August 31, 2005
Human Molecular Genetics 2005 14(20):2981-2990;
doi:10.1093/hmg/ddi328 PubMed Citation
Articles by Nikali, K.
Articles by Peltonen, L.
(c) The Author 2005. Published by Oxford University Press. All rights
reserved. For Permissions, please email:
journals.permissions@oxfordjournals.org
Infantile onset spinocerebellar ataxia is caused by recessive
mutations in mitochondrial proteins Twinkle and Twinky
Kaisu Nikali1,*,{dagger}, Anu Suomalainen2, Juha Saharinen1, Mikko
Kuokkanen1, Johannes N. Spelbrink3, Tuula Lönnqvist4 and Leena
Peltonen1
1Department of Molecular Medicine, National Public Health Institute
and 2Department of Medical Genetics, Programme of Neurosciences,
University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290
Helsinki, Finland, 3Institute of Medical Technology, Tampere
University Hospital, University of Tampere, 33014 Tampere, Finland and
4Department of Child Neurology, Hospital for Children and Adolescents,
Helsinki University Central Hospital, Stenbäckinkatu, 00250 Helsinki,
Finland
* To whom correspondence should be addressed. Tel: +44 2078486549;
Fax: +44 2078486816; Email: kaisu.nikali@tiscali.co.uk
Received February 21, 2005; Revised July 29, 2005; Accepted August 24,
2005
Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a
severe autosomal recessively inherited neurodegenerative disorder
characterized by progressive atrophy of the cerebellum, brain stem and
spinal cord and sensory axonal neuropathy. We report here the
molecular background of this disease based on the positional
cloning/candidate approach of the defective gene. Having established
the linkage to chromosome 10q24, we restricted the critical DNA region
using single nucleotide polymorphism-based haplotypes. After analyzing
all positional candidate transcripts, we identified two point
mutations in the gene C10orf2 encoding Twinkle, a mitochondrial
deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice
variant Twinky, underlying IOSCA. The founder IOSCA mutation,
homozygous in all but one of the patients, leads to a Y508C amino acid
change in the polypeptides. One patient, heterozygous for Y508C,
carries a silent coding region cytosine to thymine transition mutation
in his paternal disease chromosome. This allele is expressed at a
reduced level, causing the preponderance of messenger RNAs encoding
Y508C polypeptides and thus leads to the IOSCA disease phenotype.
Previously, we have shown that different mutations in this same gene
cause autosomal dominant progressive external ophthalmoplegia (adPEO)
with multiple mtDNA deletions (MIM 606075), a neuromuscular disorder
sharing a spectrum of symptoms with IOSCA. IOSCA phenotype is the
first recessive one due to Twinkle and Twinky mutations, the dominant
PEO mutations affecting mtDNA maintenance, but in IOSCA, mtDNA stays
intact. The severe neurological phenotype observed in IOSCA, a result
of only a single amino acid substitution in Twinkle and Twinky,
suggests that these proteins play a crucial role in the maintenance
and/or function of specific affected neuronal subpopulations.
- Nervenarzt.
2005 Sep 21; [Epub ahead of print] Related Articles, Links
[Ataxias Diagnostic procedure and treatment.]
Klockgether T.
Klinik fur Neurologie, Universitatsklinikum Bonn, .
Ataxia disorders (or
ataxias) include both hereditary and
nonhereditary diseases of the cerebellum and spinal cord, all of which
are clinically characterized by progressive ataxia. A distinction is
made between ataxia disorders and focal diseases of the cerebellum
(tumor, abscess, infarction, hemorrhage, demyelinating disease).
Ataxias are classified according to the molecular causes, being
divided into hereditary ataxias, sporadic degenerative ataxias, and
acquired ataxias. The diagnostic tests to be applied should be
selected to suit the individual clinical situation in each case. When
a patient experiences disease onset before the age of 25 years and the
disease affects only one generation autosomal recessive ataxias must
be considered. If one of the patient's parents had a similar disease
spinocerebellar ataxia (SCA) with a dominant autosomal mode of
inheritance is probable. Patients with sporadic disease starting in
adulthood may have an acquired ataxia, such as alcoholic cerebellar
degeneration (ACD) or paraneoplastic cerebellar degeneration (PCD), or
a sporadic degenerative ataxia, such as multiple system atrophy (MSA)
or sporadic adult-onset ataxia (SAOA). Therapies based on the
underlying molecular pathogenesis are available for a number of ataxia
disorders.
PMID: 16175415 [PubMed - as supplied by publisher]
- NEUROLOGY
2005;65:922-924
(c) 2005 American Academy of Neurology
Brief Communications
Quality of life in patients with Charcot–Marie–Tooth disease
P. Vinci, MD, M. Serrao, MD, PhD, A. Millul, MD, A. Deidda, MD, F. De
Santis, MD, S. Capici, MD, D. Martini, MD, F. Pierelli, MD and V.
Santilli, MD
From the Department of Physical Medicine and Rehabilitation (Drs.
Vinci, Deidda, De Santis, Capici, and Santilli) and the Rehabilitation
Unit, Polo Pontino-ICOT (Drs. Serrao and Pierelli), University "La
Sapienza," Rome; Italian Charcot-Marie-Tooth Association, Rome
(Drs.
Vinci and Martini); and "Mario Negri" Institute, Milan, Italy
(Dr.
Millul).
Address correspondence and reprint requests to Dr. Mariano Serrao,
Department of Neurology and Otolaryngology, Viale dell'Università 30,
00185, Rome, Italy; e-mail: jackmarian@mclink.it
The authors evaluated quality of life in Charcot–Marie–Tooth disease
by administering the Medical Outcome Study Short Form-36 (SF-36)
questionnaire to 121 Italian patients. Patients scored lower on all of
the SF-36 scales compared with Italian normative data. Scores were
lower in nonworking vs working patients, women vs men, and older vs
younger patients, but not between patients with demyelinating vs
axonal forms or between patients who had undergone orthopedic foot
surgery vs those who had not.
- Immunobiology.
2005;210(5):279-82.
Rapid molecular diagnosis of ataxia-telangiectasia by
optimised
RT-PCR and direct sequencing analysis.
Mancebo E, Pacho A, de Pablos P, Munoz-Robles J,
Castro MJ, Romo
E, Morales P, Gonzalez L, Paz-Artal E, Allende LM.
Servicio de Inmunologia, Hospital Universitario 12 de
Octubre,
Ctra. Andalucia km 5.4, 28041-Madrid, Spain.
Ataxia-telangiectasia (A-T)
is a severe autosomal recessive
disorder involving cerebellar degeneration, immunodeficiency,
chromosomal instability, radiosensitivity, and cancer predisposition.
A-T results from mutations in a single gene (ataxia-telangiectasia
mutated, ATM) on chromosome 11 that encodes a 3056 amino acid protein
(ATM). The purpose of this study is the design of an easy and rapid
method for the molecular diagnosis of A-T which could be applied to
clinical diagnosis, genetic counselling, carrier prediction, and
prenatal diagnosis. Sixteen primer pairs were designed for RT-PCR. The
PCR conditions were optimised to obtain a unique profile for the
amplification of the 16 PCR products. These fragments were purified,
directly sequenced and interpreted. The mutations found in three
Spanish A-T families were reconfirmed with the optimised PCR and
direct sequencing analysis. Up to now more than 400 A-T associated
mutations have been reported in the ATM gene that do not support the
existence of one or several hotspots. The immense size (transcript
with 9168 nucleotides) and the structure of this gene (66 exons)
greatly complicate the process of screening for all sequence
variations. Our simple method allows identification of mutations in
the coding region of the ATM gene from cDNA and represents a very
useful tool for early diagnosis and genetic counselling in families
with A-T.
PMID: 16164035 [PubMed - in process]
- Leukemia.
2005 Sep 15; [Epub ahead of print]
Relation between genetic variants of the ataxia
telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome
and predisposition to childhood T-lineage acute lymphoblastic
leukaemia.
Meier M, den Boer ML, Hall AG, Irving JA, Passier M,
Minto L, van
Wering ER, Janka-Schaub GE, Pieters R.
1Department of Paediatric Oncology/Haematology,
Erasmus MC/Sophia
Children's Hospital, Erasmus University Medical Centre, Rotterdam, The
Netherlands.
The T-lineage phenotype in children with acute
lymphoblastic
leukaemia (ALL) is associated with in vitro drug resistance and a
higher relapse-risk compared to a precursor B phenotype. Our study was
aimed to investigate whether mutations in the ATM gene occur in
childhood T-lineage acute lymphoblastic leukaemia (T-ALL) that are
linked to drug resistance and clinical outcome. In all, 20 different
single nucleotide substitutions were found in 16 exons of ATM in
62/103 (60%) T-ALL children and 51/99 (52%, P=0.21) controls. Besides
the well-known polymorphism D1853N, five other alterations (S707P,
F858L, P1054R, L1472W, Y1475C) in the coding part of ATM were found.
These five coding alterations seem to occur more frequently in T-ALL
(13%) than controls (5%, P=0.06), but did not associate with altered
expression levels of ATM or in vitro resistance to daunorubicin.
However, T-ALL patients carrying these five coding alterations
presented with a higher white blood cell count at diagnosis (P=0.05)
and show an increased relapse-risk (5-year probability of disease-free
survival (pDFS)=48%) compared to patients with other alterations or
wild-type ATM (5-year pDFS=76%, P=0.05). The association between five
coding ATM alterations in T-ALL, their germline presence, white blood
cell count and unfavourable outcome may point to a role for ATM in the
development of T-ALL in these children.Leukemia advance online
publication, 15 September 2005; doi:10.1038/sj.leu.2403943.
PMID: 16167060 [PubMed - as supplied by publisher]
- Eur
Neurol. 2005 Jul 26;54(1):23-27 [Epub ahead of print]
Degree of Cerebellar Ataxia Correlates with
Three-Dimensional
MRI-Based Cerebellar Volume in Pure Cerebellar Degeneration.
Richter S, Dimitrova A, Maschke M, Gizewski E, Beck
A, Aurich V, Timmann D.
Department of Neurology, University of
Duisburg-Essen, Essen, Germany.
The aim of the present study
was to compare the severity of
cerebellar ataxia as measured by the International Cooperative Ataxia
Rating Scale (ICARS) by Trouillas et al. [ J Neurol Sci
1997;145:205-211] with the cerebellar volume in chronic cerebellar
disease. Fifteen patients with pure cerebellar degeneration were
investigated. Seven patients suffered from spinocerebellar ataxia type
6, 5 from idiopathic late-onset cerebellar ataxia, 2 from autosomal
dominant cerebellar ataxia type III and 1 from episodic ataxia type 2.
Volumetric analysis was based on individual three-dimensional MR
images. Total ICARS score significantly inversely correlated with the
cerebellar volume (r = -0.805, p < 0.0001), correlations between
ICARS
subscores and cerebellar volume were significant for upper and lower
limb ataxia, ataxia of posture and gait, and dysarthria, but not for
the oculomotor subscore. The results suggest that the degree of
cerebellar atrophy in pure cerebellar degenerative disorders is
accompanied by comparable functional impairment (i.e. degree of
cerebellar ataxia). Copyright (c) 2005 S. Karger AG, Basel.
PMID: 16088175 [PubMed - as supplied by publisher]
- Over the course of the
past few decades, it has become apparent that
in contrast to previously held beliefs, the adult central nervous
system (CNS) may have the capability of regeneration and repair. This
greatly expands the possibilities for the future treatment of CNS
disorders, with the potential strategies of treatment targeting the
entire scope of neurological diseases. Indeed, there is now ample
evidence that stem cells exist in the CNS throughout life, and the
progeny of these stem cells may have the ability to assume the
functional role of neural cells that have been lost. The existence of
stem cells is no longer in dispute. In addition, once transplanted,
stem cells have been shown to survive, migrate, and differentiate.
Nevertheless, the clinical utility of stem cell therapy for
neurorestoration remains elusive. Without question, the control of the
behavior of stem cells for therapeutic advantage poses considerable
challenges. In this paper, the authors discuss the cellular signaling
processes that influence the behavior of stem cells. These signaling
processes take place in the microenvironment of the stem cell known as
the niche. Also considered are the implications attending the
replication and manipulation of elements of the stem cell niche to
restore function in the CNS by using stem cell therapy.
Overview
The treatment of CNS disorders has traditionally been limited by the
belief that, unlike other tissue such as the skin or liver, the CNS is
not capable of repair and regeneration. Over the course of the past
few decades, however, it has become apparent that the adult CNS may in
fact have the capability of repair and regeneration. The concept of
neurorestoration refers to the replacement of cellular and structural
elements that have been lost, and consequent restoration of
function.[2,5,8,26,32,36,37]
The disease processes that represent potential targets for this mode
of therapy span the scope of neurological disorders. For example,
neurodegenerative disorders such as Parkinson disease have been the
focus of tremendous attention.[2,5] Huntington disease is another
potential target. Patients with white matter and demyelinating
diseases such as multiple sclerosis could also benefit from the
replacement of the cellular elements that contribute the myelin
sheaths of axon tracts. Suppression of seizures in patients with
epilepsy and recovery of function after stroke have also been
identified as potential goals. Furthermore, pediatric patients
suffering from abnormal neurodevelopment and victims of traumatic
injury to the brain, spinal cord, and peripheral nerves could benefit
from this treatment, with possible restoration of normal function.
Cellular transplantation therapy is one strategy that plays a central
role in neurorestoration.[5] In the past, efforts to increase the
levels of dopamine in the basal ganglia to treat Parkinson disease led
workers to transplant adrenal medullary grafts.[2,3] In addition,
progenitors harvested from fetal tissue have been used as a source of
transplantable neural precursor cells. Unfortunately, the
transplantation of primary tissue would require the preparation of
graft material from multiple fetuses for each patient. Clearly, the
limited availability of fetal tissue and the moral and ethical
objections to its use present serious social and political barriers to
its further exploration and development, and most certainly to its
future widespread clinical application.
In the search for another source of tissue for transplantation, stem
cells have received a tremendous amount of attention, both in the
scientific and in the popular literature. Broadly defined, stem cells
are multipotent entities that are capable of self-renewal and
proliferation into the differentiated cells of tissues and organs. In
the nervous system, the NSCs would differentiate into all the cellular
elements of the CNS, including neuronal subtypes, oligodendroglia,
astrocytes, Schwann cells, and neural crest derivatives such as
smooth-muscle cells.
Two general categories of stem cells (embryonic and adult) have been
identified as potentially capable of generating adequate quantities of
graft material for practical utility. Embryonic stem cells that are
derived from the inner cell mass of the embryonic blastula could be
clonogenically expanded to yield large quantities of tissue to treat
multiple patients. Furthermore, consistent with the initial findings,
stem cells have been identified in certain areas of the adult brain.
Therefore, it appears that neurogenesis persists well into adulthood,
and that these adult stem cells could potentially be mobilized to
migrate and differentiate to replace cells that have been lost. This
could be accomplished either in vivo, directly from the natural niches
of these stem cells in the brain, or after in vitro modification or
clonogenic expansion.
Little question remains about the existence of NSCs. Furthermore,
there is now little doubt that stem cells can be harvested and
transplanted, after which they survive, migrate, differentiate, and in
some animal models even appear to ameliorate "neurological
deficits."
In addition, there is even evidence that NSCs can be induced to
"activate" in response to insults.[15,24] Nevertheless, the
clinical
utility of stem cell therapy for neurorestoration remains elusive.
Without question, the control of the behavior of stem cells for
therapeutic advantage poses considerable challenges. In this paper, we
discuss the cellular signaling processes that influence the behavior
of stem cells. These signaling processes take place in the
microenvironment of the stem cell known as the niche. Our ultimate
ability to use stem cells effectively for therapeutic purposes may
hinge on our understanding and manipulation of these signaling
processes.
Cellular Signaling and Nsc Behavior
During the normal process of CNS development, multipotent neural
precursors determine cell fate and migrate to form the familiar and
appropriate layers and patterns. These choices are determined by a
combination of intrinsic and extrinsic signals.[6] Intrinsic signals
can be regarded as preprogrammed subroutines in the genetic program of
the precursor cells. These subroutines are activated and modulated by
a sequential pattern of spatially and temporally organized extrinsic
signals. The identity and temporal and spatial order of these
intrinsic and extrinsic signals has been the subject of extremely
active investigation in the field of neuroembryology, and many
signaling paradigms have already been elucidated.
Several general signaling modalities exist. In the process of
inductive signaling, adjacent cells acquire different fates through
their selective exposure to locally acting extrinsic signals. In a
slight modification, gradient signaling refers to the dose-dependent
response to extrinsic signals by adjacent cells, with more proximal
cells experiencing a higher signal concentration and thus choosing a
fate different from that of cells more distal to the signal source.
With a higher degree of complexity, the cells providing the signal to
the neural precursors may themselves be subject to an antagonist
signal provided by yet another cell. In combinatorial signaling,
precursor cells choose fates in response to two separate signals.
Finally, in the contact-mediated modality of lateral signaling, small
relative differences between signals provided by interacting cells are
amplified in a feedback mechanism to cause dramatic differences in the
fates chosen by the signaling cells.
Similar to the processes known to exist in normal neuroembryological
development, intrinsic and extrinsic signals are important in stem
cell differentiation and migration.[1,11,13,14,23] In response to
local environmental cues, decisions are made regarding fate.[8] Stem
cells exist in niches in which extrinsic signals modulate the
intrinsic signals that drive self-renewal and determination of cell
fate.[16,18,29,30,35] Figure 1 shows a simplified schematic of a stem
cell in its niche. The extrinsic signals found in the niche can be
soluble signals from either a distant (Fig. 1A) or a local source
(Fig. 1B). Examples of soluble signals include stem cell mitogens such
as fibroblast growth factor–2[25] a glycosylated form of the cysteine
protease inhibitor cystatin C, epidermal growth factor,[9]
neuregulin-1, bone morphogenetic proteins,[17,18,27] and the
transforming growth factor–β and Wnt families of signaling
proteins.[28] In addition to soluble factors, contact-mediated factors
such as the Notch signaling system can regulate cell fate (Fig. 1C).
Finally, proteins such as β1 integrins found in the
extracellular
matrix (Fig. 1D) are another important modality of contact-mediated
signaling in stem cell niches.[33,35] In the presence of multiple
cues, the cell integrates the signals (Fig. 1E)[1] and chooses
self-renewal or a pathway of differentiation.[8]
Consideration of the Notch signaling system demonstrates some of the
elements of signaling through integral membrane proteins. Notch is a
very strong extrinsic signaling modality that has been shown to be an
important determinant of cell fate during development[4,10] in a wide
spectrum of tissue types, from the hematopoietic system to the CNS,
and it has been evolutionarily conserved across species. Neighboring
cells in developing tissues communicate through Notch signals to
direct cell fate decisions. Neighbors may be equivalent or biased in
response to other signals so that one cell is the signaler and the
other is the receiver. This process segregates specific cell lineages
from clusters and helps define borders. It is also important in the
maintenance of the differentiated state and has been implicated in
neoplastic processes such as leukemia and cervical cancer.
Furthermore, defects in its ligand and receptor are known to be
important in the Alagille and cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy congenital
syndromes, respectively. Most importantly for neurorestoration,
however, it is the strongest known signal for gliogenesis, and appears
to be of paramount importance in the choice of fates between neurons
and glia.[7,21,22,28,31,34]
The Notch receptor was first characterized in Drosophila melanogaster
and is known to be a 300-kD single-pass transmembrane receptor. The
extracellular domain contains 36 tandem epidermal growth factor–like
repeats and three cysteine-rich LIN-12/Notch repeats. The
intracellular domain consists of six tandem ankyrin repeats, a
glutaminerich domain (opa), and a PEST sequence. The intracellular and
extracellular domains of the Notch receptor are noncovalently linked,
as indicated in the schematic drawing (Fig. 1). Similar receptors have
been identified across species, including the nematode Caenorhabditis
elegans, sea urchins, and vertebrates, including rodents and humans.
The ligands to the Notch receptor belong to the DSL family of
transmembrane proteins. This ligand family is defined by the unique
DSL domain near the amino terminus of the proteins. In addition to the
DSL domain, these ligands also contain tandem epidermal growth factor
repeats of varying numbers, a cysteine-rich region, a transmembrane
domain, and a nonfunctional intracellular domain. Similar to the Notch
receptor, DSL ligands have been identified in organisms that span the
phylogenetic scale, including humans. Known DSL ligands include Delta
and Serrate in D. melanogaster, LAG-2 and APX-1 in C. elegans, xDelta1
in Xenopus spp., mDeltalike1 and mSerrate1 in mice, and rJagged in
rats. In addition, hDelta1, hJagged1, and hJagged2 have been
identified in humans. Comparisons of DSL proteins across species show
remarkable conservation, indicating an important role that has been
persistent over time.[10]
Implications for Restorative Neurosurgery
With the therapeutic application of NSCs for neurorestoration in mind,
a clearer picture is emerging. Both in normal neurodevelopment and
stem cell biology, the precursor cells display preprogrammed behavior
modified by cues from the local environment. The fundamental
assumption is that differentiation and predictable behavior of NSCs
can be achieved if the appropriate cocktail of soluble/ diffusible or
contact-mediated signals is present. In addition, several corollary
considerations are quickly evident. For example, can we use NSCs from
different sources in an equivalent fashion? The answer to this
important question requires that we understand the developmental
potential of all the types of NSCs.
This understanding may not be achievable with the Methods currently
available for the study and isolation of NSCs. After NSCs are
harvested and identified, they are clonogenically expanded in floating
cultures outside of their natural niches. Stem cells are known to
change and dedifferentiate over time in the absence of normal
environmental cues.[1] Therefore, their developmental potential may be
hopelessly obscured outside of their niches. In addition, even if the
stem cells maintain their developmental potential when eventually
transplanted, their long-term fate and thus therapeutic efficacy may
depend on the environmental signals present in the transplantation
site. The stem cells may need to be modified in vitro prior to
transplantation and deliberately programmed to differentiate along
certain lines.[8,12] Alternatively, after transplantation, the
neighboring cells in the transplantation site and eventual integration
sites may need to train the new stem cells, and the efficacy of the
therapy may depend on the effectiveness of the training.[19,20]
Furthermore, in the normal embryological process, the extrinsic signal
that determines appropriate development is organized not only
temporally but also spatially, with a three-dimensional matrix of
graded positional signals that is obviously absent in current in vitro
systems, and it is perhaps also absent in vivo at the target site of
therapy.
Conclusions
Given these considerations, it would appear that our ability to use
NSCs effectively for therapeutic purposes may be critically dependent
on our ability to manipulate the signals that determine stem cell
behavior in a temporal and spatially appropriate fashion, both at the
treatment target site and during the in vitro processing before
transplantation. Fortunately, this is an area of extremely active
investigation, with new signaling modalities and ways to manipulate
them being elucidated. The promise of NSCs may ultimately be realized
not merely by their existence, but also by our ability to control
their behavior. For neurosurgeons, this may mean that the
microenvironment into which stem cells are transplanted may be as
important as the cells themselves and the anatomical target.
Abbreviation Notes
CNS = central nervous system; DSL = Delta, Serrate, LAG-2; NSC =
neural stem cell.
Reprint Address
Charles Y. Liu, M.D., Ph.D., 1200 North State Street #5046, Los
Angeles, California 90033.
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