Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.

Download Full-text

In vivo molecular signatures of cerebellar pathology in spinocerebellar ataxia type 3

10.1101/2020.01.03.894337 ◽

2020 ◽

Author(s):

Maria do Carmo Costa ◽

Maria Radzwion ◽

Hayley S. McLoughlin ◽

Naila S. Ashraf ◽

Svetlana Fischer ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Resonance Spectroscopy ◽

Phospholipid Membrane ◽

Spinocerebellar Ataxia Type 3 ◽

Noninvasive Biomarkers ◽

Type 3 ◽

Mediated Reduction

AbstractBackgroundNo treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of aspects of disease pathology recapitulated by animal models.ObjectiveWe sought to identify shared neurochemical signatures in two mouse models of SCA3 that reflect aspects of the human disease pathology.MethodsCerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by magnetic resonance spectroscopy at 9.4 tesla. Motivated by the shared neurochemical abnormalities in the two models, we determined the levels of neurofilament medium (NFL, indicator of neuroaxonal integrity) and myelin basic protein (MBP, indicator of myelination) in cerebellar lysates from a subset of mice and from patients with SCA3. Finally, NFL and MBP levels were measured in cerebellar extracts of Q84/Q84 mice upon sustained silencing of the mutant ATXN3 gene from 6-8 weeks-of-age until death.ResultsBoth Q84/Q84 and Q135 mice displayed lower N-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lower myo-inositol and total choline, indicating disturbances in phospholipid membrane metabolism and demyelination. Cerebellar NFL and MBP levels were accordingly lower in both models as well as in the cerebellar cortex of patients with SCA3 than controls. Furthermore, long-term sustained RNAi-mediated reduction of ATXN3 levels increased NFL and MBP in Q84/Q84 cerebella.ConclusionsN-acetylaspartate, myo-inositol and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, which are reversible by reduction of mutant ATXN3 levels.

Download Full-text

In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3

Movement Disorders ◽

10.1002/mds.28140 ◽

2020 ◽

Vol 35 (10) ◽

pp. 1774-1786 ◽

Cited By ~ 1

Author(s):

Maria do Carmo Costa ◽

Maria Radzwion ◽

Hayley S. McLoughlin ◽

Naila S. Ashraf ◽

Svetlana Fischer ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Molecular Signatures ◽

Spinocerebellar Ataxia Type 3 ◽

Type 3

Download Full-text

In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3

Journal of Neurochemistry ◽

10.1111/jnc.13606 ◽

2016 ◽

Vol 138 (1) ◽

pp. 150-162 ◽

Cited By ~ 16

Author(s):

Jana Schmidt ◽

Thorsten Schmidt ◽

Matthias Golla ◽

Lisa Lehmann ◽

Jonasz Jeremiasz Weber ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Therapeutic Drug ◽

Spinocerebellar Ataxia Type 3 ◽

Type 3 ◽

In Vivo Assessment

Download Full-text

Clinical Findings of Type 3 Spinocerebellar Ataxia

10.5327/1516-3180.198 ◽

2021 ◽

Author(s):

Juliano Henrique Rocha Filho ◽

Beatriz Brasil Braga ◽

Kristine Leão Alarcão ◽

Maria Teresa Aires Cabral Dias

Keyword(s):

Spinocerebellar Ataxia ◽

Clinical Findings ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxias ◽

Gene Modification ◽

Spinocerebellar Ataxia Type 3 ◽

The Common ◽

Cerebellar Peduncle ◽

Type 3 ◽

Extrapyramidal Motor

Background: Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of progressive autosomal disorders of dominant inheritance with a gradual degeneration of the cerebellum and related pathways [1]. This leads to a movement disorder, loss of balance and coordination, accompanied by slurred speech [2]. Among the approximately 40 types of SCA, the spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most clinically heterogeneous [3]. It involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems [2]. Objectives: Understand the clinical findings of SCA3. Methods: The review was based on papers from SciELO and LILACS databases. Articles presented in full, written in English or Portuguese, were researched. Results: SCA3 is a consequence of the ATXN3 gene modification, which generates pathogenic repeated expansions of trinucleotides CAG, leading to polyglutamine coding. The common clinical phenotype includes the presentation of symptoms such as cerebellar ataxia, ophthalmoplegia, spasticity, basal ganglia symptoms, sensory symptoms, amyotrophy, including facial atrophy and fasciculations [4]. In addition, atrophy of the cerebellar vermis, hemispheres, brainstem and medial cerebellar peduncle are visualized on MRI in the early stages, resulting in an enlargement of the fourth ventricle. Furthermore, changes also occur in the caudate nucleus, putamen and upper cerebellar peduncle [5]. Conclusion: Through data analysis, there is a necessity to know the clinical and pathological characteristics of SCA3. This neurological disorder causes suffering for the patients, since it is a highly debilitating serious condition.

Download Full-text

Mitochondrial impairment in patients with spinocerebellar ataxia type 3

Aktuelle Neurologie ◽

10.1055/s-2004-833082 ◽

2004 ◽

Vol 31 (S 1) ◽

Author(s):

L Schöls ◽

J Andrich ◽

H Przuntek ◽

K Müller ◽

J Zange

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Mitochondrial Impairment ◽

Type 3

Download Full-text

Faculty Opinions recommendation of Oculomotor deficits in spinocerebellar ataxia type 3: Potential biomarkers of preclinical detection and disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727305821.793552233 ◽

2018 ◽

Author(s):

Alexandra Durr

Keyword(s):

Disease Progression ◽

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Type 3 ◽

Potential Biomarkers

Download Full-text

Faculty Opinions recommendation of Caffeic acid and resveratrol ameliorate cellular damage in cell and Drosophila models of spinocerebellar ataxia type 3 through upregulation of Nrf2 pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732321491.793552234 ◽

2018 ◽

Author(s):

Alexandra Durr

Keyword(s):

Caffeic Acid ◽

Spinocerebellar Ataxia ◽

Cellular Damage ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Nrf2 Pathway ◽

Type 3 ◽

Drosophila Models

Download Full-text

A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

Cell Death and Disease ◽

10.1038/s41419-021-03444-x ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Zhefan Stephen Chen ◽

Xiaoying Huang ◽

Kevin Talbot ◽

Ho Yin Edwin Chan

Keyword(s):

Spinocerebellar Ataxia ◽

E3 Ligase ◽

Spinocerebellar Ataxia Type ◽

Disease Genes ◽

Spinocerebellar Ataxia Type 3 ◽

E3 Ligases ◽

Protein Ubiquitination ◽

Polyq Protein ◽

Polyq Diseases ◽

Type 3

AbstractPolyglutamine (polyQ) diseases comprise Huntington’s disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin–proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.

Download Full-text