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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.

Background Charcot-Marie-Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound heterozygous mutations in a gene that encodes ganglioside-induced differentiation-associated protein-1 (GDAP1). GDAP1 is located on 8q21, and plays a major role in ganglioside differentiation and Schwann cell function, as well as regulates neuronal and axonal development. Case presentation In this study, we recruited a consanguineous south Indian family with an affected patient, an unaffected sibling, and the mother. The patient was affected with progressive weakness in the lower and upper limbs, atrophy of small muscles of the foot and hands, club shaped hands, steppage gait, hoarseness, and decreased muscle tone. His nerve biopsy examination revealed peripheral nerve demyelination and nerve conduction testing confirmed a reduction in nerve activities, while MRI showed mild degenerative changes in the cervical spine. Further, targeted exome sequencing (TES) and copy number variation analysis were performed on the patient. TES identified a compound heterozygous mutation that includes a missense mutation and a 3'UTR mutation (NM_018972.4: c.413A > G:p.His138Arg; g.74488790C > A:c.*29C > A, respectively) in GDAP1. The missense change is not reported in available public databases, while the UTR variant is seen only in the South Asian population in gnomAD (allele frequency = 0.00002). Multiple in silico prediction tools show that the missense mutation is damaging. Subsequently, in silico protein modeling, phylogenetic conservation analysis, and the impact of the mutation on the canonical transcript have also been performed. The compound heterozygous mutation was confirmed in the patient by PCR-Sanger sequencing and was shown to segregate within the family. Conclusions The combined results support the fact that these two mutations in GDAP1 link the genotype-phenotype correlation in the family. This will help the family in genetic testing, counseling, and early diagnosis. Our findings support expanded phenotypic characterization along with the genetic spectrum of GDAP1 mutations in CMT type4A in the Indian population.

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson’s disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case–control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373 T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808 T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson’s disease progression, and to enhance diagnostic capabilities.

Charcot-Marie-Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound heterozygous mutations in a gene that encodes ganglioside-induced differentiation-associated protein-1 (GDAP1). GDAP1 is located on 8q21, and plays a major role in ganglioside differentiation and Schwann cell function, as well as regulates neuronal and axonal development. The combined results support the fact that these two mutations in GDAP1 link the genotype-phenotype correlation in the family. This will help the family in genetic testing, counseling, and early diagnosis. Our findings support expanded phenotypic characterization along with the genetic spectrum of GDAP1 mutations in CMT type4A in the Indian population.

A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration. Graphical abstract