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:
- N-terminal domain (NTD) - The beginning of an amino acid sequence of a protein which contains an amine group (-NH2)
- Nuclear localization signal (NLS) - a peptide sequence tag in a protein which directs the protein containing this sequence to be imported into the cell nucleus
- Non-homologous end-joining (NHEJ) - a double strand DNA break repair pathway which does not require a homologous template to repair the DNA damage
- DNA double-stranded breaks (DSB) -
- Neurite outgrowth - a crucial process in that takes place during embryonic development and neurogenesis whereby neuron, during differentiation, grow dendrite and axon projections from their cell bodies; outgrowth of dendrites and axons is guided by cues such as nerve growth factor signals
- Nonsense-mediated mRNA decay
- rho guanine nucleotide exchange factor (RGNEF) interaction with TDP-43\cite{Droppelmann2019}
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