Molecular Mechanisms, Proteinopathies and Therapeutic Strategies in Neurodegenerative Disorders

L.   K.   Sengupta; S.      Sengupta

Abstract

In the evolutionary context, alterations in the basic DNA structure and fidelity of repair endow the genome with dynamism not only to survive but also to flourish. The genomic variation tools presented by evolution such as small tandem repeats (STRs), variable number of tandem repeats (VNTRs) and trinucleotide repeats (TNRs) are the most interesting. Cloning of several disease genes have identified the basic DNA structure instability attributed to nucleotide repeats in the form of changes in the tract length, threshold value, secondary structure formation, interruptions, mismatch repairs, the gene and its sequence involved as the basis for manifestation of a pathological phenotype, particularly several neurological disorders. The neurodegenerative disorders (NDDs) are chronic and progressive, characterized by selective and symmetric loss of neurons in motor, sensory and cognitive systems. The genetic anomalies that are responsible for these diseases are varied and complex. The observations on the disease age - of - onset with the length of expansion provided a strong indication that a novel toxic property of the altered protein or lack of expression of protein(s) is associated with the pathology. The conditions that ultimately lead to neuronal death, probably by apoptosis, involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases include Huntingtons disease, Machado-Joseph disease and amylotropic lateral sclerosis among trinucleotide disorders and other NDDs like Alzheimers disease (AD) and Parkinsons disease (PD) seems to be shared. Presently, there are very few means to impede the disease progression, as there is loss of specific neuronal cell population in different disorders. The investigations on each aspect of these disorders will bring tremendous clinical benefits, offering better classification of the diseases and thus facilitating early diagnosis and genetic counseling. This review briefly summarizes research work directed towards understanding the pathophysiology of neurological disorders at the molecular level and highlights the trends in the current and future therapeutic approaches. Although the goal of delaying the onset of brain disorders may be within the grasp of modern medicine, there are several critical barriers to progress. Traditionally, in drug discovery, testing, and development, a combination of models, including in vivo, in vitro, transgenic, animal and microbial models is used. Advances in computer technology, in the form of “in silico” modeling systems, is there to complement currently available models and enable investigators to simulate alternative strategies to modulate neural function in a dynamic interactive mode and are expected to accelerate the drug discovery process. Understanding the complexities of the cellular pathology of the multistep, multifactorial diverse group of NDDs and associated paraphernalia of structural and functional alterations leading to proteinopathies would provide an opportunity for designing rational approaches for therapeutic regimen towards effective treatment. Successful discovery and development of therapeutic regimen will improve and reduce hospitalization and long-term care costs and suffering.

Keywords: Proteinopathies, Alzheimer, neurodegenerative

« Previous Next »