Neurodegeneration, a term that refers to the progressive loss of structure and function of neurons, is a feature of many neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models. As such, the investigation of TDP-43 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP-43 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP-43 as a common therapeutic approach to treat neurodegenerative diseases.

Skeletal muscles undergo atrophy in response to diseases and aging. Here we report that mitofusin 2 (Mfn2) acts as a dominant suppressor of neuromuscular synaptic loss to preserve skeletal muscles. Mfn2 is reduced in spinal cords of transgenic SOD1 and aged mice. Through preserving neuromuscular synapses, increasing neuronal Mfn2 prevents skeletal muscle wasting in both SOD1 and aged mice, whereas deletion of neuronal Mfn2 produces neuromuscular synaptic dysfunction and skeletal muscle atrophy. Neuromuscular synaptic loss after sciatic nerve transection can also be alleviated by Mfn2. Mfn2 coexists with calpastatin largely in mitochondria-associated membranes (MAMs) to regulate its axonal transport. Genetic inactivation of calpastatin abolishes Mfn2-mediated protection of neuromuscular synapses. Our results suggest that, as a potential key component of a novel and heretofore unrecognized mechanism of cytoplasmic protein transport, Mfn2 may play a general role in preserving neuromuscular synapses and serve as a common therapeutic target for skeletal muscle atrophy.

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson’s disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Inclusion body myositis (IBM) is the most common cause of primary myopathy in individuals ages 50 years and over, and is pathologically characterized by protein aggregates of p62 and mislocalized cytoplasmic TDP-43 as well as mitochondrial abnormalities in affected muscle fibers. Our recent studies have shown the accumulation of TDP-43 in mitochondria in neurons from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), and revealed mitochondria as critical mediators of TDP-43 neurotoxicity. In this study, we investigated the association between mitochondria and TDP-43 in biopsied skeletal muscle samples from IBM patients. We found that IBM pathological markers TDP-43, phosphorylated TDP-43, and p62 all coexisted with intensively stained key subunits of mitochondrial oxidative phosphorylation complexes I-V in the same skeletal muscle fibers of patients with IBM. Further immunoblot analysis showed increased levels of TDP-43, truncated TDP-43, phosphorylated TDP-43, and p62, but decreased levels of key subunits of mitochondrial oxidative phosphorylation complexes I and III in IBM patients compared to aged matched control subjects. This is the first demonstration of the close association of TDP-43 accumulation with mitochondria in degenerating muscle fibers in IBM and this association may contribute to the development of mitochondrial dysfunction and pathological protein aggregates.

Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.