Amyotrophic lateral sclerosis and frontotemporal lobar degeneration

1. Amyotrophic lateral sclerosis & Frontotemporal lobar degeneration summary :
Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that
specifically affects the function and survival of motor neurons in the motor cortex, brainstem and
spinal cord. ALS is a rare disorder with progressive muscle weakness and paralysis causes severe
motor impairment. On the other hand, in FTLD (frontotemporal lobar degeneration), cortical
neurons in the frontal and anteriotemporal cortex of the brain degenerate. FTLD patients can
present a spectrum of clinical presentations including behavioral variant frontotemporal dementia
(bvFTD), progressive nonfluent aphasia, while clinical manifestations are progressive changes in
personality, behavior, insight, judgment, reasoning abilities.
Both FTLD and ALS are heterogeneous at the clinical, neuropathological and genetic levels and,
even though they come across as distinct progressive disorders, but recent ages researchers are
uncovering both diseases shared common spectrum pathology. In most ALS and FTLD cases,
the predominant pathological species are RNA-binding proteins. To date, Both ALS and FTLD
has been linked to mutations in a set of genes (TARDBP, FUS, MAPT, GRN, VCP, CHMP2B,
C9ORF72). The aim of both review paper is to describe the two disorders from genetic point of
view, to highlight commonalities and overlapping features for advancements in clinical trials and
treatment procedures.
Paper entitled with “Inside out: the role of nucleocytoplasmic transport in ALS and FTLD”
address whether defects in nuclear transport are indeed implicated in the disease or not. This
paper combined original articles and bioinformatic analyses to find both RNA-binding proteins
and nuclear transport factors are key players in ALS/FTLD pathology. This paper includes a set
of genes which is important for maintaining protestasis, cytoskeleton, nuclear transport and RNA
metabolism. The set of genes with heterogenous functions but bioinformatics analysis has found
all genes are interlinked and the network analysis revels that the set of genes categorized within
motor neuron spectrum specially ALS. Analysis of network bridge reveals most of genes are
associated with transport of protein, ‘transport of RNA’ along with ‘axonal transport’ clearly
suggesting that ribonuclear transport in synaptic axons contributing to the both ALS and FTLD
pathogenesis.
Paper entitled with “A network of RNA and protein interactions in Fronto Temporal Dementia”
outlined several genes (TARDBP, FUS, MAPT, GRN, VCP, CHMP2B, C9ORF72) functions
and how mutation of those gene contributes to RNA processing and post-transcriptional
regulation of gene expression.
TDP-43, an RNA-binding protein TAR DNA-binding protein 43 (TDP43) has role in mRNA
transport. TDP-43 is one of the major proteins are highly associated with ALS & FTD in nearly
all ALS patients (~97 %) and patients of the FTLD-TDP subtype (~45 %). At least 60 mutation,
both downregulation and accumulation of TDP-43 protein imbalances cellular integrity, causes
loss of muscle, inability to control movement and finally drive neurodegeneration. Genetically
engineered TDP-43 structure eliminates both its ability to bind RNA and different aspect of
processing mRNA, and cause nerve cell death in models of ALS and FTD. TDP-43 is
extensively phosphorylated and cleaved to produce toxic, aggregate prone C-terminal fragments.

2. Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein
are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause
of FTD. FUS, a multifunctional protein able to bind and interact with single stranded RNA and
double stranded DNA, participating in different aspects of as mRNA transport, mRNA stability
and translation RNA metabolism. Structural and functional similarities between FUS and another
ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA
processing in ALS/FTD, and this pathway is now a major focus of interest. Interestingly
endogenous FUS is maintained at full length, even in disease so that neurodegeneration is
induced through the presence of a single point mutation within the FUS gene.
Mutation in the Glycine rich region and C-terminal part of FUS gene underlying the ALS
pathogenesis related to FUS nucleus/cytoplasmic imbalance. immunostaining of FUS in
postmortem ALS brain samples found its increased localization in the cytoplasm.
Tau is a microtubule-associated protein which is found in abundance in the axons of Central
nervous system (CNS) and Peripheral nervous system (PNS). Tau involves in assembling and
stabilizing microtubule, where microtubule help to maintain cell shape, assist cell division and
transport material within cells. Mutations also lead to alteration of splicing at the mRNA level,
so imbalances the protein level and depending on RNA level which decides the fate of onset of
neurodegeneration. FTLD is characterized by abnormal phosphorylated tau deposition. In ALS
both upper motor neurons & lower motor neurons observed tau pS396 in nucleus and cytoplasm.
C9orf72 protein is abundant in nerve cells (neurons) in the outer layers of the brain (cerebral
cortex) and functions in the regulation of intracellular trafficking processes in the endosomal and
autophagy-lysosomal compartments in neuronal cell lines also found to colocalize with ubiquitin.
Mutation in C9orf72 gene reduces C9orf72 protein lead to an impaired waste cleaning process in
cells and, ultimately, to the accumulation of toxic products in the cells.
Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause
frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation.
The major implication observed upon mutations of genes which lead to splice defects highlights
the relevance of regulation at RNA level which decides the fate of onset of neurodegeneration.
The gain of toxic functions, the loss of functional function, RNA binding site altered or lost non-
coding RNA, RNA splicing, nucleocytoplasmic transport all is interlinked for the pathogenesis
of ALS & FTLD neurodegenerative diseases. Unique integration and network analysis of those
genes might help to develop new and more effective therapeutic approaches.