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The progressive loss of structure and function of neurons causes various neurodegenerative diseases which need to be examined using measurable indicators, known as biomarkers. Proteins are the building blocks for the cell and are essential as they participate in many processes in the cells. When biologically essential proteins are impaired, it leads to devastating consequences in humans and mammals among which the most prominent is neurodegenerative disease. Proteins conform to three-dimensional structures to enable their functions. Besides, some proteins have the tendency to form self-assembly structures. When these self-assembly proteins assume abnormal conformation, they accumulate and cause pathological conditions. The genetic and molecular origins of protein misfolding in association with their relationship with neurodegeneration and aging are being studied to better understand and develop treatments. Accumulations of these misfolded proteins form aggregates which is considered as the most prominent cause of many neurodegenerative diseases. This article reviews the misfolded proteins in various neurodegenerative diseases and analyzes the diverse aspects of protein misfolding as a potential agent of biomarkers with an approach for finding an inhibitor for misfolding. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease with the typical manifestations of involuntary movements, psychiatric and behavior disorders, and cognitive impairment. It is caused by the dynamic mutation in CAG triplet repeat number in exon 1 of huntingtin ( HTT) gene. The symptoms of HD especially the age at onset are related to the genetic characteristics, both the CAG triplet repeat and the modified factors. Here, we reviewed the recent advancement on the genotype-phenotype relationship of HD, mainly focus on the characteristics of different expanded CAG repeat number, genetic modifiers, and CCG repeat number in the 3′ end of CAG triplet repeat and their effects on the phenotype. We also reviewed the special forms of HD (juvenile HD, atypical onset HD, and homozygous HD) and their phenotype-genotype correlations. The review will aid clinicians to predict the onset age and disease course of HD, give the genetic counseling, and accelerate research into the HD mechanism. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant genetic disease characterized by cerebellar dysfunction associated with slow saccades, early hyporeflexia, severe tremor of postural or action type, peripheral neuropathy, cognitive disorders, and other multisystemic features. SCA2, one of the most common ataxias worldwide, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the ATXN2 gene, which results in the incorporation of a segment of polyglutamines in the mutant protein, being longer expansions associated with earlier onset and more sever disease in subsequent generations. In this review, we offer a detailed description of the clinical manifestations of SCA2 and compile the experimental evidence showing the participation of ataxin-2 in crucial cellular processes, including messenger RNA maturation and translation, and endocytosis. In addition, we discuss in the light of present data the potential molecular mechanisms underlying SCA2 pathogenesis. The mutant protein exhibits a toxic gain of function that is mainly attributed to the generation of neuronal inclusions of phosphorylated and/or proteolytic cleaved mutant ataxin-2, which might alter normal ataxin-2 function, leading to cell dysfunction and death of target cells. In the final part of this review, we discuss the perspectives of development of therapeutic strategies for SCA2. Based on previous experience with other polyglutamine disorders and considering the molecular basis of SCA2 pathogenesis, a nuclei-acid-based strategy focused on the specific silencing of the dominant disease allele that preserves the expression of the wild-type allele is highly desirable and might prevent toxic neurodegenerative sequelae. [ABSTRACT FROM AUTHOR]