Progressive muscular atrophy (PMA), which may be regarded as form of ALS, affects primarily LMN and, in some patients, also UMN.  Primary lateral sclerosis (PLS) is a slowly progressive motor neuron disease that affects upper neurons, and is more readily managed than ALS and also may not necessarily decrease overall lifespan. Frontotemporal dementia (FTD), the second most common form of early-onset dementia, following Alzheimer's disease, alters personality, behavior, language and mental functions, and has a life expectancy of 6-8 years with the first onset of symptoms.
Alzheimer's Disease (AD); Perry Syndrome ; Parkinson's Disease; Lewy body dementia; Huntington’s disease, and chronic traumatic encephalopathy; limbic predominant age-related TDP-43 encephalopathy (LATE)    .    

The role of TDP-43 in ALS group of neurodegenerative diseases

Mutations and epigenetic variations of TDP-43 and other ALS-linked genes in familial and sporadic neurodegenerative diseases 

There are at least 60 known mutations in the TDP-43 gene which have been identified in ALS (ref). Certain mutations in this gene are responsible for the development of several other neurodegenerative disorders. These include primary lateral sclerosis, progressive muscular atrophy and frontotemporal dementia (FTD). Yet, TDP-43 mutations only account for an estimated 5-10 % of familial ALS (fALS) patients \cite{Prasad_2019}⁠, while the remainder of fALS mutations occur in other ALS-linked genes. The most well-characterized of ALS-linked genes are the superoxide dismutase (SOD1), chromosome 9 open reading frame 72 (C9ORF72) , and fused in sarcoma (FUS) genes. For fALS-associated genes, all are inherited in a autosomal dominant fashion. 

TDP-43 gain-of-function: sequestering of TDP-43 in cytoplasm and formation of aggregates

In ALS there is a perturbation in TDP-43 trafficking between the nucleus and cytoplasm. The TDP-43 protein is predominantly localized to the nucleus under normal endogenous conditions. However, sequestration of the protein in the cytoplasm, results in loss of endogenous TDP-43 function and to the accumulation of insoluble cytoplasmic aggregates. Evidence suggests that the N-terminal domain (NTD) of TDP-43 proteins, a region which contains its nuclear localization signal, homodimerizes with its protein partners and appears important in its function of targeting splicing of RNA. In fact, mutation of the nuclear localization or nuclear export signals results in cytoplasmic or nuclear aggregate formation \cite{Winton_2008}⁠, whereas exogenous accumulation of cytoplasmic TDP-43 has been demonstrated to be specifically cytotoxic in primary rat cortical neurons. TDP-43 has also been reported to be sequestered in the cytoplasm by co-aggregation with other proteins, such as poly(GR) \cite{Nagano2020}. Therefore, homeostatic auto-regulation of TDP-43 is critical for its normal function. Normally, TDP-43 binds to the 3’ UTR of its own pre-mRNA, which leads to its undergoing of nonsense-mediated mRNA decay \cite{Ayala_2010}, thereby decreasing the nuclear to cytoplasmic shuttling of the transcript as well as its corresponding translation in the functional protein \cite{Koyama_2016}. Loss of homeostasic nucleo-cytoplasmic localization resulting in either nuclear or cytoplasmic TDP-43 aggregates appears critical is the pathology of all variants of ALS. Pathogenic TDP-43 inclusion bodies, becomes cleaved at the C-terminus, ubiquitinated and hyperphyphorylated, and targeted for autophagosomal removal (Chang et al., 2016)⁠.

TDP-43 loss-of-function: loss of normal DNA and RNA processing functions

TDP-43 is an important protein, which is normally enriched in the nucleus, where it binds to both DNA and RNA. Some of the normal functions of the protein include the regulation of transcription, mRNA splicing and RNA stability and transports, as well as additional functions in translation. The attenuation of these critical cell processes is implicated in a variety of neurological disorders, and it has been argued  \cite{Vanden2014}  that the loss of normally functioning TDP-43 is of primary cause of neuropathology, while that toxic formation of aggregates is a secondary pathological feature, arising from protein conformational changes. The abnormal tertiary structural changes form oligomers of repeating units that result in higher order structures, which accumulate  in specific brain regions, such as motor neurons.  

TDP-43 represents a promising therapeutic target

TDP-43 remains a promising therapeutic target even when a patient does not have a mutation event 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}.