Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI’s major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI's major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change

Defining the Molecular Pathogenesis of the Neurodegenerative Disease Spinoecerebellar Ataxia Type 7

Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase with established effects in countering age-related diseases, including neurodegeneration, yet the basis for Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder in which CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene produce cerebellar degeneration in affected human patients. As transcription dysregulation likely contributes to SCA7 pathogenesis, we performed transcriptome analysis on SCA7 mice, observed downregulation of genes controlling calcium flux, and documented abnormal calcium-dependent membrane excitability in both SCA7 mouse cerebellum and SCA7 patient-derived neuronal cells. Transcription factor binding site analysis of SCA7 down-regulated genes revealed sites for peroxisome proliferator-activated receptors, which are known Sirt1 targets, and we detected marked cerebellar changes in NAD+ metabolism that are known to reduce Sirt1 function. We then crossed Sirt1 transgenic mice with two different SCA7 mouse models, and observed amelioration of cerebellar neurodegeneration, calcium flux defects, and membrane excitability in Sirt1-SCA7 bigenic mice. Finally we detected a direct functional interaction between Sirt1 and Atxn7 protein, which persisted in the presence of polyQ-expanded Atxn7 and correlated with increased turnover of Sirt1. These findings indicate that Sirt1 achieves neuroprotection by promoting proper calcium regulation, reinforce an emerging view that cerebellar ataxias exhibit altered calcium homeostasis due to metabolic dysregulation, and suggest a normal role for a Sirt1-Atxn7 interaction that is perturbed in SCA7

Defining the Molecular Pathogenesis of the Neurodegenerative Disease Spinoecerebellar Ataxia Type 7

Sirtuin 1 (Sirt1) is a NAD+-dependent protein deacetylase with established effects in countering age-related diseases, including neurodegeneration, yet the basis for Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder in which CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene produce cerebellar degeneration in affected human patients. As transcription dysregulation likely contributes to SCA7 pathogenesis, we performed transcriptome analysis on SCA7 mice, observed downregulation of genes controlling calcium flux, and documented abnormal calcium-dependent membrane excitability in both SCA7 mouse cerebellum and SCA7 patient-derived neuronal cells. Transcription factor binding site analysis of SCA7 down-regulated genes revealed sites for peroxisome proliferator-activated receptors, which are known Sirt1 targets, and we detected marked cerebellar changes in NAD+ metabolism that are known to reduce Sirt1 function. We then crossed Sirt1 transgenic mice with two different SCA7 mouse models, and observed amelioration of cerebellar neurodegeneration, calcium flux defects, and membrane excitability in Sirt1-SCA7 bigenic mice. Finally we detected a direct functional interaction between Sirt1 and Atxn7 protein, which persisted in the presence of polyQ-expanded Atxn7 and correlated with increased turnover of Sirt1. These findings indicate that Sirt1 achieves neuroprotection by promoting proper calcium regulation, reinforce an emerging view that cerebellar ataxias exhibit altered calcium homeostasis due to metabolic dysregulation, and suggest a normal role for a Sirt1-Atxn7 interaction that is perturbed in SCA7

Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.

Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7

Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

Sirtuin 1 (Sirt1) is a NAD(+)-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD(+) depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD(+) repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD(+) dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets

Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease

Summary: Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7. : Ward et al. document altered metabolism and mitochondrial dysfunction in SCA7 patients, mice, and human stem cell-derived neurons. They link these abnormalities to reduced nicotinamide adenine dinucleotide in specific subcellular compartments. Given the role of mitochondrial impairment in neurodegeneration, their results have therapeutic implications for SCA7 and related neurological disorders. Keywords: spinocerebellar ataxia, polyglutamine, trinucleotide repeat, mitochondria, oxidative metabolism, nicotinamide adenine dinucleotide, Purkinje cell, ataxin-7, mouse model, induced pluripotent stem cell