Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Synofzik, Matthis; Puccio, Hélène; Mochel, Fanny; Schöls, Lüdger

doi:10.1016/j.neuron.2019.01.049

Cited by 98 publications

(109 citation statements)

References 164 publications

(159 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Other neurological dysfunctions and/or non-neurologic phenotypes have also been reported in some cases. Among the different forms of recessive ataxia, Friedreich’s ataxia (FRDA) has the highest prevalence and is the most studied (Synofzik et al, 2019). In regard to prevalence FRDA is followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay, ataxia with vitamin E deficiency, autosomal recessive cerebellar ataxia types 1 and 2, and ataxia with oculomotor apraxia types 1 and 2 (Noreau et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

et al. 2019

View full text Add to dashboard Cite

A biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences. However only the biallelic AAGGG expansions were reported to cause late-onset ataxia. In this study, we aimed to assess the prevalence and nature of RFC1 repeat expansions in three cohorts of adult-onset ataxia cases: Brazilian (n = 23) and Canadian (n = 26) cases that are negative for the presence of variants in other known ataxia-associated genes, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the biallelic AAGGG expansion in only one Brazilian family which presented two affected siblings, and in one Canadian case. We also observed two new repeat conformations, AAGAG and AGAGG, which suggests the pentanucleotide expansion sequence has a dynamic nature. To assess the frequency of these new repeat conformations in the general population, we screened 163 healthy individuals and observed the AAGAG expansion to be more frequent in cases than in control individuals. While additional studies will be necessary to asses the pathogenic impact of biallelic genotypes that include the novel expanded conformations, their occurrence should nonetheless be examined in future studies.

show abstract

Section: Introductionmentioning

confidence: 99%

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The finding that hPSC-PCs upregulated mitochondrial gene sets after the formation of synapses with GCs and emergence of calcium firing properties is consistent with a role for mitochondria in calcium buffering and local, activity driven protein synthesis in large output neurons (52). The importance of mitochondria to PCs has been well demonstrated in mouse models and is related directly or indirectly to many autosomal recessive cerebellar ataxias (53). Our findings identify P0-P7 as the time when mitochondrial genes are highly upregulated during mouse PC development and suggest that hPSC-PCs will be useful for studying human PC mitochondrial disorders.…”

Section: Discussionmentioning

confidence: 59%

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics

Buchholz

Carroll

Kocabas

et al. 2020

Preprint

View full text Add to dashboard Cite

Comparative transcriptomics between differentiating human pluripotent stem cells (hPSC) and developing mouse neurons offers a powerful approach to compare genetic and epigenetic pathways in human and mouse neurons. To analyze human Purkinje cell (PC) differentiation, we optimized a protocol to generate hPSC-PCs that formed synapses when cultured with mouse cerebellar glia and granule cells and fired large calcium currents, measured with the genetically encoded calcium indicator jRGECO1a. To directly compare global gene expression of hPSC-PCs with developing mouse PCs, we used translating ribosomal affinity purification (TRAP). As a first step, we used Tg(Pcp2-L10a-Egfp) TRAP mice to profile actively transcribed genes in developing postnatal mouse PCs, and used metagene projection to identify the most salient patterns of PC gene expression over time. We then created a transgenic Pcp2-L10a-Egfp

show abstract

“…With additional clinical data and the advent of new molecular, cellular, and preclinical models to study CHIP function, it is likely that precision-based approaches could be developed based on the specific mutation or the specific loss of function. Finally, by looking more broadly at the various autosomal recessive ataxias, additional themes and targets that could be effective across multiple ataxia diseases may also come to light in the years to come (37).…”

Section: Discussionmentioning

confidence: 99%

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Madrigal

McNeil

Sanchez‐Hodge

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Monogenetic disorders that cause cerebellar ataxia are characterized by defects in gait and atrophy of the cerebellum; however, patients often suffer from a spectrum of disease, complicating treatment options. Spinocerebellar ataxia autosomal recessive 16 (SCAR16) is caused by coding mutations in STUB1, a gene that encodes the multifunctional enzyme CHIP (C terminus of HSC70-interacting protein). The disease spectrum of SCAR16 includes a varying age of disease onset, cognitive dysfunction, increased tendon reflex, and hypogonadism. Although SCAR16 mutations span the multiple functional domains of CHIP, it is unclear whether the location of the mutation and the change in the biochemical properties of CHIP contributes to the clinical spectrum of SCAR16. In this study, we examined relationships between the clinical phenotypes of SCAR16 patients and the changes in biophysical, biochemical, and functional properties of the corresponding mutated protein. We found that the severity of ataxia did not correlate with age of onset; however, cognitive dysfunction, increased tendon reflex, and ancestry were able to predict 54% of the variation in ataxia severity. We further identified domain-specific relationships between biochemical changes in CHIP and clinical phenotypes and specific biochemical activities that associate selectively with either increased tendon reflex or cognitive dysfunction, suggesting that specific changes to CHIP–HSC70 dynamics contribute to the clinical spectrum of SCAR16. Finally, linear models of SCAR16 as a function of the biochemical properties of CHIP support the concept that further inhibiting mutant CHIP activity lessens disease severity and may be useful in the design of patient-specific targeted approaches to treat SCAR16.

show abstract

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Cited by 98 publications

References 164 publications

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

Contact Info

Product

Resources

About