A5060249985- Amyotrophic Lateral Sclerosis Research
- Genetic Neurodegenerative Diseases
- Neurogenetic and Muscular Disorders Research
- Prion Diseases and Protein Misfolding
- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Neurological diseases and metabolism
- Cholinesterase and Neurodegenerative Diseases
- Hereditary Neurological Disorders
- Pasture and Agricultural Systems
- S100 Proteins and Annexins
- DNA Repair Mechanisms
- Histone Deacetylase Inhibitors Research
- Muscle Physiology and Disorders
- biodegradable polymer synthesis and properties
- Autophagy in Disease and Therapy
Mayo Clinic in Florida
2016-2024
Jacksonville College
2018-2022
Mayo Clinic in Arizona
2022
WinnMed
2018
Yale University
2013-2015
Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence TMEM106B rs3173615 protective genotype was associated longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting slower disease course. The seminal discovery filaments derived from is common feature aging and, across range neurodegenerative disorders,...
Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the
Loss-of-function mutations in the progranulin gene (GRN), which encodes (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis white matter an accumulation myelin debris microglial lysosomes same regions. Accumulation also observed patients with FTD. In addition, our findings suggest...
Abstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence Alzheimer’s disease (AD). Approximately, 30–70% AD cases present proteinopathy (AD-TDP), and a greater severity compared to patients pathology. However, it remains unclear what extent dysfunction is involved in pathogenesis. Methods To investigate whether prominent feature AD-TDP cases, we evaluated...
A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). remarkably similar intronic TG3C2 associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, can undergo repeat-associated non-ATG (RAN) translation to dipeptide proteins (DPRs). Yet, these diseases result degeneration distinct subsets neurons. We show that expression mice sufficient...
Polyglutamine diseases are dominantly inherited neurodegenerative caused by an expansion of a CAG trinucleotide repeat encoding glutamine tract in the respective disease-causing proteins. Extensive studies have been performed to unravel disease pathogenesis and develop therapeutics. Here, we report on several lines evidence demonstrating that Nemo-like kinase (NLK) is key molecule modulating toxicity spinocerebellar ataxia type 1 (SCA1), polyglutamine protein ATAXIN1 (ATXN1). Specifically,...
Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One the disease-specific features TDP-43 inclusions is aberrant phosphorylation at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems FTD/ALS patient samples. Specifically, identified three mAbs (26H10, 2E9 23A1) from spleen B cell...
Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes pathogenesis across multiple model systems. Most remarkably, loss of one copy Nlk rescues phenotypes mice, including extending lifespan. We also investigated molecular which NLK...
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited cerebellar caused by the expansion of polyglutamine (polyQ) repeat in gene encoding ATXN3. The polyQ induces protein inclusion formation neurons patients and results neuronal degeneration cerebellum other brain regions. We used adeno-associated virus (AAV) technology to develop new mouse model SCA3 that recapitulates several features human disease, including locomotor defects, cerebellar-specific loss, polyQ-expanded ATXN3...
The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results accumulation toxic dipeptide (DPR) proteins central nervous system We have found that, among sense DPR proteins, HDAC6 specifically interacts with poly (GA) co-localizes inclusions both patient tissue mouse model this disease (c9FTD/ALS). Overexpression increased levels cultured cells independently...