Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis

Abstract

Neurodegenerative diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to experience exponential growth thanks to numerous advancements in technology, shifts in the understanding of the disease as a phenomenon, and the change in the perspective regarding gene editing and the advantages of this action. The aim of this paper is to analyze the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We intend through this review to focus on the newest treatment, diagnosis, and predictions regarding this large group of diseases, in order to obtain a more accurate analysis and to identify the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide evidence of future possible novel therapies that target the specific genes and that could be useful to be taken into consideration when the classical approaches fail to shed light.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; biomarkers; epigenetics; gene expression; molecular genetics; molecular pathology; neurodegenerative disease; therapeutic targets.

Figure 1

Amyloid precursor protein (APP) is a protein that spans the cell membrane. Its processing can occur through two pathways: the non-amyloidogenic (A) and amyloidogenic (B) pathways. In the non-amyloidogenic pathway, APP is cleaved in the middle of Aβ by α-secretase, resulting in the production of soluble APPα (sAPPα) and C-terminal fragment α (CTFα), which is then hydrolyzed by γ-secretase to generate the APP intracellular domain (AICD). In the amyloidogenic pathway, APP is cleaved by β-secretase, resulting in the release of N-terminal soluble APPβ (sAPPβ) and the C-terminal fragment β (CTFβ), which is then hydrolyzed by γ-secretase to produce Aβ and AICD. γ-secretase is composed of several parts, including presenilin, nicastrin, anterior pharynx-defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). Mutations in the PSEN gene may increase the activity of γ-secretase, leading to the formation of plaques. Moreover, the plaques lead to lysosomal dysfunction (interacting with Caspaze 2/3), promoting cleavage of Tau and NFT (neurofibrillary tangles) formation. Created with BioRender.com.

Figure 2

The huntingtin protein can take on various forms and undergo changes depending on the expression of the HTT gene. Normally, the expression of HTT results in the production of an RNA transcript that codes for the complete huntingtin protein. However, if the gene has an expanded CAG repeat, the RNA transcript can be processed abnormally, producing an mRNA that encodes only the HTT exon1 protein. 1 & 2—Transcription and Processing; 3 & 4—Translation; 5—Proteolysis. Created with BioRender.com.

Figure 3

Advances in large-scale genomic analysis have uncovered a variety of causative genes and risk factors for amyotrophic lateral sclerosis (ALS). These gene variants map onto key pathogenic mechanisms relevant to all motor neuron cellular compartments as well as neighboring cells such as glia and interneurons. In this way, these mechanisms are genetically validated, enabling a greater confidence in their targeting for therapeutic benefit. Some of these mechanisms have emerged only in recent years due to new genetic information, including gene changes highlighting dysregulation of RNA processing and metabolism. There is significant overlap of some genes with those found in closely related disorders such as frontotemporal dementia (for example, C9orf72, CHCHD10, SQSTM1, TBK1, CCNF, FUS, TARDBP, OPTN, UBQLN2, TUBA4A, ATAXN2, VCP, and CHMP2B). This suggests a closer relationship with broader neurodegenerative disorders, and indeed many of the pathways depicted are relevant in, for example, Alzheimer’s disease. ER, endoplasmic reticulum. Created with BioRender.com.