TDP-43 loss of function in muscle

Introduction

TAR DNA-binding protein 43 (TDP-43) is a critical protein involved in various cellular processes, including RNA metabolism. Its dysfunction, particularly loss of function, has been implicated in several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Recent research has also explored the role of TDP-43 in muscle function and pathology.

Key Insights

Essential Role in Development and Motor Function:
- TDP-43 is crucial for normal embryonic development and viability. Mice lacking TDP-43 die early in embryogenesis, while heterozygous mice show motor disturbances and muscle weakness without motor neuron degeneration.
- Loss of TDP-43 in spinal cord motor neurons leads to ALS-like phenotypes, including motor dysfunction, muscle weakness, and motor neuron loss, indicating its essential role in motor neuron survival and function.
Muscle-Specific Effects:
- TDP-43 dysfunction in muscle cells causes age-related motor abnormalities and sarcoplasmic aggregates, leading to behavioral deficits and premature lethality in Drosophila models.
- TDP-43 forms amyloid-like oligomeric assemblies called myo-granules during muscle regeneration, which are essential for normal muscle formation but can seed pathological aggregates in neuromuscular diseases.
Tissue-Specific Behavior:
- TDP-43 displays tissue-specific behavior, targeting unique transcripts in muscle and neuronal cells. This differential targeting is influenced by cell-specific expression of RNA-binding proteins, contributing to disease development in a tissue-specific manner.
Reversibility of Pathological Effects:
- Suppression of mutant TDP-43 expression in mouse models after disease onset can lead to significant recovery of motor function, muscle re-innervation, and extended lifespan, suggesting that the pathological effects of TDP-43 dysfunction are at least partially reversible .

Conclusion

TDP-43 is essential for both embryonic development and the maintenance of motor function. Its dysfunction, particularly in muscle cells, leads to significant motor abnormalities and muscle pathology. The protein exhibits tissue-specific behavior, which contributes to its role in disease development. Importantly, the pathological effects of TDP-43 dysfunction can be partially reversed, offering potential therapeutic avenues for conditions like ALS and FTLD.

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TDP-43 loss of function in muscle

Summary

Introduction

Key Insights

Conclusion

Sources and full results

Does a loss of TDP-43 function cause neurodegeneration?

Loss of TDP-43 function, rather than a gain of function, may cause neurodegeneration in ALS and FTLD, suggesting a loss-of-function mechanism.

Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43

Removal of cytoplasmic TDP-43 in new mouse models of ALS/FTLD-TDP can lead to neuron preservation, muscle re-innervation, and functional recovery.

Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis

TDP-43 is essential for viability and mild reduction in its function can cause motor deficits without degeneration of motor neurons.

Cell environment shapes TDP-43 function with implications in neuronal and muscle disease

TDP-43 dysfunction contributes to disease development in a tissue- and disease-specific manner, with unique transcripts targeted in both neuronal and muscle cells.

Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes

Drosophila TDP-43 dysfunction leads to loss-of-function phenotypes, impairing synaptic transmission and motor control, ultimately causing age-related neurodegeneration.

Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD

TDP-43 dysfunction in glia and muscle cells contributes to the pathogenesis of TDP-43-related ALS and FTLD, with potential direct targets being the glutamate transporters EAAT1/2.

Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis-like Phenotypes in Mice*

TDP-43 is essential for the survival and functioning of mammalian spinal cord motor neurons, and loss of TDP-43 function could be a major cause for neurodegeneration in ALS with TDP-43 proteinopathies.

Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats.

Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats, with partial recovery of motor function when the transgene is switched off.

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

TDP-43 forms amyloid-like myo-granules during muscle regeneration, which may be the source of cytoplasmic TDP-43 aggregates in neuromuscular diseases.

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Short-term suppression of A315T mutant human TDP-43 expression in mice with neurodegeneration significantly improves motor and behavioral deficits and reduces astrogliosis, suggesting potential for future treatments.

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