Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder that causes progressive problems with vision, movement, and balance. Individuals with SCA7 have CAG-polyglutamine repeat expansions in one of their genes; these expansions lead to progressive neuronal death in the cerebellum. ATXN7, the protein encoded by the culprit gene is actually a subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons. These two highly vulnerable neuronal cell types are severely affected in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms.
However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, SCA7 has no cure or disease-modifying therapies. Therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development. New research has shed light on the origins of SCA7 and demonstrates effective new therapeutic pathways for SCA7 and the more than 40 other types of spinocerebellar ataxia. The study, which appears online on the website of the journal Neuron, implicates metabolic dysregulation leading to altered calcium homeostasis in neurons as the underlying cause of cerebellar ataxias. Scientists of the Duke University performed transcriptome analysis on mice living with SCA7. These mice displayed down-regulation of genes that controlled calcium flux and abnormal calcium-dependent membrane excitability in neurons in their cerebellum. The team also linked dysfunction of the protein Sirtuin 1 (Sirt1) in the development of cerebellar ataxia.
Sirt1 is a “master regulator” protein associated both with improved neuronal health and with reduced overall neurodegenerative effects associated with aging. La Spada’s team observed reduced activity of Sirt1 in SCA7 mice; this reduced activity was associated with depletion of NAD+, a molecule important for metabolic functions and for catalyzing the activity of numerous enzymes, including Sirt1. When the team crossed mouse models of SCA7 with Sirt1 transgenic mice, they found improvements in cerebellar degeneration, calcium flux defects, and membrane excitability. They also found that NAD+ repletion rescued SCA7 disease phenotypes in both mouse models and human stem cell-derived neurons from patients. These findings elucidate Sirt1’s role in neuroprotection by promoting calcium regulation and describe changes in NAD+ metabolism that reduce the activity of Sirt1 in neurodegenerative disease. NAD is known to regulate mitochondria for energy production and is a cofactor for proteins that remodel DNA and maintain neuronal differentiation, like the nuclear enzyme CtBP1.
Al La Spada, MD, PhD, professor of Neurology, Neurobiology, and Cell Biology, at the Duke School of Medicine, and the study’s senior author, concluded: “Sirt1 has been known to be neuroprotective, but it’s a little unclear as to why. Tying NAD+ metabolism and Sirt1 activity to a crucial neuronal functional pathway offers a handful of ways to intervene that could be potentially useful and practical to patients. This study not only tells us about how SCA7 begins at a basic mechanistic level, but it also provides a variety of therapeutic opportunities to treat SCA7 and other ataxias”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in CLinical Biochemistry.
McLoughlin HS et al. Neurobiol Dis. 2019 Oct 24; 134:104635.
Niewiadomska-Cimicka A et al. Neurotherapeutics 2019 Aug 20.
Ward JM et al., La Spada AR. Cell Rep. 2019; 26(5):1189-1202.
Dott. Gianfrancesco Cormaci
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