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Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

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Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10–15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digenetic/polygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimer’s disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype–phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.

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Abbreviations

fALS:

Familial amyotrophic lateral sclerosis

fFTD:

Familial frontotemporal dementia

sALS:

Sporadic amyotrophic lateral sclerosis

sFTD:

Sporadic frontotemporal dementia

TARDBP :

TAR DNA-binding protein-43

TDP-43 :

TAR DNA-binding protein 43

HIV-1:

Human immunodeficiency virus

c9orf72:

Chromosome 9 open reading frame 72

FUS :

Fused in sarcoma

SQSTM1 :

Sequestrome-1

SOD1 :

Superoxide dismutase 1

GRN :

Granulin

MAPT :

Microtubule-associated protein tau

VCP :

Valosin-containing protein

PFN1 :

Profilin1

TBK1 :

TANK-binding kinase

CCNF :

Cyclin F

KIF5A :

Kinesin family member 5A

GLT8D1 :

Glycosyltransferase 8 domain containing 1

NEK1 :

NIMA-related kinase 1

CHMP2B:

Charged multivesicular body protein 2B

CHCHD10:

Coiled-coil-helix-coiled-coil-helix domain containing 10

WGS:

Whole-genome sequencing

WES:

Whole-exome sequencing

GWAS:

Genome-wide association studies

RAN:

Repeat-associated non-AUG

DPR:

Dipeptide repeat

OPTN :

Optineurin

C21orf2 :

Chromosome 21 open reading frame 2

DNAJC7:

DnaJ heat shock protein family (Hsp40) member C7

TBP:

TATA-box binding protein

CTSF:

Cathepsin F

MFSD8:

Major facilitator superfamily domain 8

PGRN:

Glycoprotein called progranulin

TDP-43:

TAR DNA-binding protein-43

hnRNP:

Heterogeneous nuclear ribonucleoprotein

DPRs:

Dipeptide repeat proteins

TBK1:

TANK-binding kinase 1

UMN:

Upper motor neuron

LMN:

Lower motor neuron

FTLD:

Frontotemporal lobar degeneration

FTDP-17T:

Frontotemporal dementia with parkinsonism-17 T

PSP:

Progressive supranuclear palsy

CBD:

Corticobasal degeneration

NFTs:

Neurofibrillary tangles

IHC:

Immunohistochemistry

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

CJD:

Creutzfeldt-Jakob disease

UPS:

Ubiquitin–proteasome system

RRM2:

Ribonucleoside-diphosphate reductase subunit M2

VCP:

Valosin-containing protein

VAPB:

VAMP-associated protein B And C

HNRNPA1:

Heterogeneous nuclear ribonucleoprotein A1

AMPA:

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate

GABAA:

γ-Aminobutyric acid type A receptors

LLPS:

Liquid–liquid phase separation

LCD:

Low complexity domain

TUBA4A:

Tubulin Alpha 4a

ALS2:

Alsin

LAMP-2:

Lysosomal associated membrane protein-2

CTSD:

Cathepsin D

CSF:

Cerebrospinal fluid

ASOs:

Antisense oligonucleotides

CuATSM:

Diacetylbis(N(4)-methylthiosemicarbazonato) copper II

iPSCs:

Induced pluripotent stem cells

CSF:

Cerebrospinal fluid

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Funding

LK is supported by Malaviya Postdoctoral Fellowship by Institute of Eminence (IoE), Banaras Hindu University (BHU) from Ministry of Education (MoE), Government of India (GOI). Funding from IoE, BHU to MM and AM is duly acknowledged. MM is supported by SERB-Power Fellowship by Science and Engineering Research Board, GOI.

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    Laxmi Kirola, Ashim Mukherjee & Mousumi Mutsuddi

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L. K. and M. M. generated the theme for this article, and L. K. executed the literature search, tabulations, figures, data collection, and analysis. The final draft was edited and modified by L. K., A. M., and M. M.

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Kirola, L., Mukherjee, A. & Mutsuddi, M. Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Mol Neurobiol 59, 5673–5694 (2022). https://doi.org/10.1007/s12035-022-02934-z

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