TDP-43 is a promising therapeutic target

TDP-43 remains a promising therapeutic target even when a patient does not have a mutation evident in the TARDBP gene. For example, the vast majority (~95%) of ALS patients (sporatic and familial), exhibit TDP-43 neuronal inclusions in their cortical and spinal cord neurons although a mere 5-10% have TDP-43 mutations. TDP-43 was found to be a major constituent of ubiquitin-positive inclusions in ALS patients \cite{Arai_2006}. Leading to the recognition of this protein aggregate as a hallmark of ALS \cite{Wolozin_2019}

Keypoints Box:

Different types of protein aggregates / clumps:
pathologic protein aggregation at autopsy reflects pathogenesis at disease onset ? Aggregates may represent compensatory responses to cell stresses to forestall death of brain cells, rather than causal mechanisms in disease.  3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time\cite{Espay2019}.  The formation of protein inclusions is a hallmark of the disease and includes RNA-binding proteins such as TAR DNA Binding Protein (TDP-43), Fused in Sarcoma/ Translocated in Liposarcoma (FUS/TLS), TATA-Box Binding Protein Associated Factor 15 (TAF 15), Ewing Sarcoma Breakpoint Region 1 (EWS), RNA Binding Motif Protein 45 (RBM45), Heterogeneous Nuclear Ribonucleoprotein A1 and A2/B1 (hnRNPA1 and hnRNPA2B1), and Rho Guanine Nucleotide Exchange Factor (RGNEF) in Alzheimer's Disease amyloid into plaques and hyperphosphorylated tau into tangles ,    α-synuclein into Lewy bodies