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Protein folding, Misfolding, Neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Chaperone proteins, Proteostasis, Therapeutic strategies

Introduction

Neurodegenerative diseases represent a significant and growing global health burden, affecting millions worldwide. These disorders are characterized by the progressive dysfunction and loss of neurons, leading to debilitating symptoms such as cognitive decline, movement disorders, and eventual death. While the specific etiology varies among different neurodegenerative diseases, a common pathological hallmark is the accumulation of abnormally folded proteins within the brain tissue [1,2]. The process of protein folding, essential for maintaining cellular function and structure, can be disrupted by various factors, resulting in the formation of misfolded and aggregated proteins. This review aims to explore the underlying mechanisms of protein folding and misfolding in neurodegenerative diseases, focusing on Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).

Protein folding: a fundamental biological process

Protein folding is a highly orchestrated process whereby polypeptide chains adopt their three-dimensional structure, enabling them to perform specific biological functions [3]. The folding process is guided by the amino acid sequence and influenced by environmental factors such as temperature, pH, and the presence of cofactors. Proper protein folding is essential for protein stability, function, and interactions with other cellular components.

Mechanisms of protein misfolding

Despite the fidelity of the folding process, proteins can misfold and adopt alternative conformations that are prone to aggregation. Several factors contribute to protein misfolding, including genetic mutations, environmental stressors, and errors in protein synthesis and degradation pathways. Genetic mutations can predispose certain proteins to misfolding by altering their primary structure or stability, as observed in familial forms of neurodegenerative diseases such as AD and HD [4,5].

Role of misfolded proteins in neurodegenerative diseases

In neurodegenerative diseases, misfolded proteins such as amyloidbeta (Aβ) in AD, alpha-synuclein in PD, and mutant huntingtin in HD, accumulate within neurons and form insoluble aggregates [6]. These aggregates disrupt cellular homeostasis, impairing neuronal function and triggering inflammatory responses and oxidative stress. The spread of misfolded proteins between neurons, akin to prion-like propagation, further exacerbates disease progression.

Molecular chaperones and proteostasis networks

Cells possess elaborate protein quality control mechanisms, including molecular chaperones and proteases, which facilitate proper protein folding and degradation [7]. Molecular chaperones assist in the folding of nascent proteins and refolding of misfolded proteins, thereby preventing their aggregation. Disruption of chaperone function or overload of misfolded proteins can overwhelm proteostasis networks, leading to protein aggregation and neurotoxicity.

Therapeutic strategies targeting protein misfolding

Understanding the mechanisms underlying protein misfolding has paved the way for novel therapeutic approaches aimed at restoring protein homeostasis in neurodegenerative diseases. Strategies include enhancing chaperone activity, promoting protein clearance pathways such as autophagy and the ubiquitin-proteasome system, and developing small molecules or antibodies to target misfolded proteins directly.

Future directions

Advances in understanding protein folding and misfolding in neurodegenerative diseases have uncovered potential therapeutic targets and biomarkers for early diagnosis [8]. Future research efforts should focus on elucidating the complex interactions between misfolded proteins and cellular pathways, as well as developing effective interventions to halt or slow disease progression. Ultimately, the integration of basic science discoveries with clinical applications holds promise for improving outcomes and quality of life for patients affected by neurodegenerative diseases.

Results and Discussion

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain, leading to progressive neuronal dysfunction and eventual cell death [9 , 10]. The mechanisms governing protein folding and misfolding play crucial roles in the pathogenesis of these disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).

Protein misfolding in neurodegenerative diseases

In AD, the aggregation of amyloid-beta (Aβ) peptides into insoluble plaques and the accumulation of hyperphosphorylated tau protein into neurofibrillary tangles disrupt neuronal function and contribute to synaptic loss and cognitive decline. Aβ peptides, derived from the amyloid precursor protein (APP), undergo misfolding and aggregation, which are influenced by genetic factors (e.g., mutations in APP or presenilin genes) and environmental factors (e.g., oxidative stress). Tau protein, normally involved in stabilizing microtubules, misfolds due to abnormal phosphorylation and aggregates into paired helical filaments, contributing to neurotoxicity. Similarly, PD is characterized by the accumulation of alpha-synuclein protein aggregates, known as Lewy bodies, in dopaminergic neurons of the substantia nigra. Alpha-synuclein normally functions in synaptic vesicle trafficking; however, misfolding and aggregation disrupt cellular function and lead to mitochondrial dysfunction, oxidative stress, and neuronal death. Genetic mutations in the SNCA gene encoding alpha-synuclein or environmental toxins (e.g., pesticides) can exacerbate protein misfolding and aggregation in PD. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, resulting in an elongated polyglutamine tract in the huntingtin protein. Misfolded mutant huntingtin proteins form intracellular aggregates that impair proteostasis, disrupt mitochondrial function, and induce neurotoxicity, particularly affecting striatal neurons.

Mechanisms of protein misfolding

The propensity of certain proteins to misfold and aggregate arises from multiple factors. Genetic mutations, such as those observed in familial forms of neurodegenerative diseases, alter protein structure and stability, promoting misfolding. Environmental factors, including oxidative stress, inflammation, and exposure to toxins, further exacerbate protein misfolding by disrupting cellular proteostasis and promoting aggregation.

Cellular responses to protein misfolding

Cells possess intricate quality control mechanisms to manage protein folding and prevent the accumulation of misfolded proteins. Molecular chaperones, such as heat shock proteins (HSPs), facilitate the correct folding of nascent proteins and assist in refolding misfolded proteins. Chaperones are crucial for maintaining proteostasis under normal conditions and are upregulated in response to cellular stress to mitigate protein aggregation. Proteostasis networks, including the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway, play essential roles in protein degradation and clearance. The UPS targets ubiquitinated proteins for proteasomal degradation, while autophagy mediates the clearance of protein aggregates through lysosomal degradation. Dysregulation of these pathways, due to aging or disease-related factors, impairs protein homeostasis and exacerbates protein misfolding in neurodegenerative diseases.

Therapeutic strategies targeting protein misfolding

Understanding the mechanisms of protein misfolding has spurred the development of therapeutic strategies aimed at restoring proteostasis and reducing neurotoxicity in neurodegenerative diseases. Small molecules targeting protein aggregation, such as beta-sheet breakers or aggregation inhibitors, hold promise for preventing the formation of toxic protein aggregates. Immunotherapies targeting misfolded proteins, including monoclonal antibodies, aim to enhance clearance mechanisms and reduce protein burden in affected brain regions. Enhancing cellular proteostasis through the modulation of chaperone activity or promoting autophagy represents another therapeutic approach. Small molecules known as chaperone activators can stabilize chaperone proteins and facilitate protein folding, while autophagy inducers promote the clearance of protein aggregates and damaged organelles. Gene therapy strategies, such as antisense oligonucleotides or RNA interference, aim to reduce the production of toxic proteins implicated in neurodegenerative diseases. These approaches hold potential for modifying disease progression by targeting specific genetic mutations or pathways involved in protein misfolding. Future research efforts should focus on elucidating the complex interactions between misfolded proteins and cellular pathways implicated in neurodegenerative diseases. Advances in imaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), offer opportunities to visualize protein aggregates in vivo and monitor disease progression in clinical settings. Biomarkers associated with protein misfolding, including cerebrospinal fluid (CSF) markers or blood-based assays, may facilitate early diagnosis and monitoring of disease progression. Furthermore, preclinical studies using animal models of neurodegenerative diseases can provide insights into disease mechanisms and evaluate the efficacy of novel therapeutic interventions. Collaborative efforts between basic scientists, clinicians, and pharmaceutical companies are essential for translating preclinical discoveries into clinically effective treatments for patients affected by neurodegenerative diseases.

Conclusion

Neurodegenerative diseases pose significant challenges to global health, characterized by progressive neuronal dysfunction and debilitating symptoms. Central to the pathology of these disorders is the accumulation of misfolded proteins within the brain, disrupting cellular homeostasis and triggering neurotoxicity. This review has explored the intricate mechanisms underlying protein folding and misfolding in neurodegenerative diseases, highlighting key findings and therapeutic strategies aimed at mitigating disease progression. Fundamental insights into protein folding have revealed how genetic mutations, environmental factors, and aging contribute to protein misfolding and aggregation in disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aberrant aggregation of proteins such as amyloid-beta (Aβ), alpha-synuclein, and mutant huntingtin leads to neuronal damage, synaptic dysfunction, and ultimately, clinical manifestations of cognitive decline, movement disorders, and impaired motor function. Cellular responses to protein misfolding, including molecular chaperones and proteostasis networks, play critical roles in maintaining protein homeostasis. Molecular chaperones assist in the folding of nascent proteins and facilitate the refolding of misfolded proteins, while the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway ensure the timely degradation of damaged proteins and aggregates. Dysregulation of these pathways contributes to the accumulation of toxic protein species and exacerbates neurodegeneration. Therapeutic strategies targeting protein misfolding have emerged as promising approaches to combat neurodegenerative diseases. Small molecules designed to inhibit protein aggregation or promote chaperone activity aim to restore proteostasis and alleviate neurotoxicity. Immunotherapies targeting misfolded proteins seek to enhance clearance mechanisms and reduce protein burden in affected brain regions, potentially modifying disease progression. Future research directions should focus on advancing our understanding of the complex interactions between misfolded proteins and cellular pathways implicated in neurodegenerative diseases. Innovative imaging techniques and biomarkers may enable early diagnosis and monitoring of disease progression, facilitating the development of personalized therapeutic interventions. Preclinical studies using animal models and collaborative efforts across disciplines are essential for translating scientific discoveries into effective treatments for patients affected by neurodegenerative diseases. In conclusion, unraveling the mechanisms of protein folding and misfolding represents a critical step toward developing transformative therapies and improving clinical outcomes for individuals with neurodegenerative diseases. Continued research efforts hold the promise of ushering in a new era of precision medicine, where targeted interventions can halt or slow the progression of these devastating disorders, ultimately enhancing quality of life for patients and their families.

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