CRISPR advancements in correcting protein misfolding: implications for neurodegenerative disorders

Protein misfolding is a critical factor in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). This essay delves into the mechanisms of protein misfolding and aggregation, their contribution to neurodegenerative disorders, and the innovative therapeutic strategies, particularly focusing on the potential of CRISPR/Cas9 gene editing technology.

Protein Misfolding and Neurodegenerative Disorders

Neurodegenerative disorders are characterized by the progressive loss of neuronal function and structure. A common pathological hallmark of these disorders is the presence of misfolded protein aggregates. In AD, amyloid-beta (Aβ) peptides and tau proteins misfold and aggregate, leading to neuronal toxicity and cognitive decline. PD is marked by the accumulation of alpha-synuclein, forming Lewy bodies that disrupt cellular homeostasis. HD results from the expansion of polyglutamine (polyQ) tracts in the huntingtin protein, causing it to aggregate and interfere with neuronal function. ALS involves the misfolding of superoxide dismutase 1 (SOD1) and other proteins, contributing to motor neuron degeneration.

The process of protein misfolding begins with the failure of molecular chaperones and the ubiquitin-proteasome system to maintain protein homeostasis. Misfolded proteins can form toxic oligomers and insoluble fibrils, which accumulate and disrupt cellular functions such as mitochondrial activity, synaptic transmission, and intracellular trafficking. The spread of these aggregates to other neurons exacerbates the disease progression.

CRISPR/Cas9 in Neurodegenerative Research

CRISPR/Cas9 technology has revolutionized genetic research and holds significant promise for treating neurodegenerative diseases. This genome-editing tool allows precise modifications of specific genes associated with these disorders. By targeting the genes responsible for the production of misfolded proteins, CRISPR/Cas9 can potentially halt or reverse disease progression.

For instance, in HD, CRISPR/Cas9 has been used to target and excise the expanded CAG repeat sequences in the huntingtin gene, thereby reducing the production of the toxic protein. Similarly, in PD, CRISPR/Cas9 can be employed to downregulate the expression of alpha-synuclein or to correct mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which is implicated in familial forms of the disease.

Moreover, CRISPR/Cas9 technology can be used to introduce protective mutations or to enhance the expression of genes that can compensate for the loss of function caused by neurodegenerative diseases. For example, increasing the expression of brain-derived neurotrophic factor (BDNF) has shown potential in protecting neurons and promoting their survival in models of AD and PD.

Challenges and Considerations

While CRISPR/Cas9 offers a promising avenue for treating neurodegenerative diseases, several challenges and considerations must be addressed. One major concern is the delivery of CRISPR/Cas9 components to the target cells in the brain. Effective delivery systems, such as viral vectors or nanoparticles, are crucial to ensure that the gene-editing machinery reaches the affected neurons without causing off-target effects or immune responses.

Another challenge is the potential for unintended genetic modifications. Off-target effects can lead to unwanted mutations, which could exacerbate disease symptoms or cause new health issues. Therefore, extensive preclinical studies and precise control over the gene-editing process are essential to minimize these risks.

Ethical considerations also play a significant role in the application of CRISPR/Cas9 technology, especially concerning germline editing and the long-term impacts of genetic modifications. Establishing robust ethical guidelines and regulatory frameworks is necessary to ensure the responsible use of this technology.

Conclusions

Protein misfolding is a central mechanism in the pathogenesis of neurodegenerative disorders, leading to the formation of toxic aggregates that disrupt neuronal function. CRISPR/Cas9 technology offers a groundbreaking approach to addressing these diseases by allowing precise genetic modifications. Despite the challenges and ethical considerations, the potential of CRISPR/Cas9 to correct disease-causing mutations and enhance protective mechanisms holds great promise for developing effective therapies for neurodegenerative disorders. Continued research and innovation in this field are crucial to unlocking the full potential of genome editing in combating these debilitating diseases.

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The study was recently published in the Gene Expression.

Gene Expression (GE) is an open-access journal. It was launched in 1991 by Chicago Medical School Press, and transferred to Cognizant Communication Corporation in 1994. From August 2022, GE is published by Xia & He Publishing Inc.   

GE publishes peer-reviewed and high-quality original articles, reviews, editorials, commentaries, and opinions on its primary research topics including cell biology, molecular biology, genes, and genetics, especially on the cellular and molecular mechanisms of human diseases. 

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