Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases with clinical and pathological overlap. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and FTLD, combined with the abnormal aggregation of these proteins, have initiated a shifting paradigm for the underlying pathogenesis of multiple neurodegenerative diseases. TDP-43 and FUS/TLS are both RNA/DNA-binding proteins with striking structural and functional similarities. Their association with ALS and other neurodegenerative diseases is redirecting research efforts toward understanding the role of RNA processing regulation in neurodegeneration.

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TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration

Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(10)70195-2.pdf

TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia

Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron.

https://jpet.aspetjournals.org/content/jpet/early/2012/06/13/jpet.112.192138.full.pdf

Mitochondrial Dysfunction in Neurodegenerative Diseases

The intracellular transport of organelles along an axon is crucial for the maintenance and function of a neuron. Anterograde axonal transport has a role in supplying proteins and lipids to the distal synapse and mitochondria for local energy requirements, whereas retrograde transport is involved in the clearance of misfolded and aggregated proteins from the axon and the intracellular transport of distal trophic signals to the soma. Axonal transport can be affected by alterations to various components of the transport machinery. Here, we review the current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases.

Axonal transport deficits and neurodegenerative diseases

RNA-binding proteins, and in particular TAR DNA-binding protein 43 (TDP43), are central to the pathogenesis of motor neuron diseases and related neurodegenerative disorders. Studies on human tissue have implicated several possible mechanisms of disease and experimental studies are now attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein. In addition, the distinct possibility of pleotropic or combined effects - in which gains of toxic properties and losses of normal TDP43 functions act together - needs to be considered.

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Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration

TDP-43 has been found in inclusion bodies of multiple neurological disorders, including amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease. Mutations in the TDP-43 encoding gene, TARDBP, have been subsequently reported in sporadic and familial ALS patients. In order to investigate the pathogenic nature of these mutants, the effects of three consistently reported TARDBP mutations (A315T, G348C and A382T) were tested in cell lines, primary cultured motor neurons and living zebrafish embryos. Each of the three mutants and wild-type (WT) human TDP-43 localized to nuclei when expressed in COS1 and Neuro2A cells by transient transfection. However, when expressed in motor neurons from dissociated spinal cord cultures these mutant TARDBP alleles, but less so for WT TARDBP, were neurotoxic, concomitant with perinuclear localization and aggregation of TDP-43. Finally, overexpression of mutant, but less so of WT, human TARDBP caused a motor phenotype in zebrafish (Danio rerio) embryos consisting of shorter motor neuronal axons, premature and excessive branching as well as swimming deficits. Interestingly, knock-down of zebrafisfh tardbp led to a similar phenotype, which was rescued by co-expressing WT but not mutant human TARDBP. Together these approaches showed that TARDBP mutations cause motor neuron defects and toxicity, suggesting that both a toxic gain of function as well as a novel loss of function may be involved in the molecular mechanism by which mutant TDP-43 contributes to disease pathogenesis.

/pdf/gain-and-loss-of-function-of-als-related-mutations-of-tardbp-1dj3upzhy4.pdf

Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS.

/pdf/misfolded-sod1-associated-with-motor-neuron-mitochondria-44i3dx1vuz.pdf

Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa−/− mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4−/−;Hexa−/−) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa−/− or Neu4−/− siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa−/− mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa−/− mice.

/pdf/mice-doubly-deficient-in-lysosomal-hexosaminidase-a-and-25vpihxxag.pdf

Samar Bel Hadj

Papers

Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo.

Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.