Cellular dysfunction in amyotrophic lateral sclerosis : investigating the role of TDP-43

T Jiang
The discovery that most pathological protein inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) contain the aggregated transactive response DNA-binding protein 43 kDa (TDP-43) has resulted in significant research investigating the role this protein may play in the progressive neurodegeneration, underlying genetic factors and molecular characteristics of these now so-called TDP-43 proteinopathies. Despite these research efforts, there is still no cure
more » ... or ALS and the two available therapeutics extend survival by mere months. ALS is the most common motor neuron disease (MND) and traditionally is characterised by selective degeneration of both upper and lower motor neurons (MNs) and the subsequent systematic destruction of the motor system. This results in a multitude of motor symptoms, including muscle weakness, spasticity, fasciculations, and eventually respiratory dysfunction and failure. Although recent research has proposed an important role for TDP-43 in the formation and maintenance of the nervous system, the molecular mechanisms underlying how TDP-43 affects pre- and post-synaptic compartments which make up neuronal connections in the motor system are not fully understood. Autosomal dominant point mutations in the TARPD gene that encodes TDP-43 are linked to both sporadic and familial ALS, indicating that alteration of TDP-43 can cause neurodegeneration directly (Yokoseki et al., 2008). One such point mutation is the A315T mutation. This ALS-linked mutation was one of the first utilised to create a mouse model of TDP-43 pathogenesis. In this model, driving human TDP-43 with the A315T point substitution mutation on the prion promotor causes a selective loss of upper motoneurons and lower motor neurons, as well as loss of function on the rotarod motor function test and muscle atrophy (Wegorzewska, Bell et al. 2009, Guo, Wang et al. 2012, Handley, Pitman et al. 2017). In the last decade the classification of ALS has transformed from being a pure MN disease to be consi [...]
doi:10.25959/100.00035056 fatcat:eibtmfdtunct3pmqojkdvm472e