Defects in Cells’ ‘Cleaning System’ May Underlie Huntington’s, Researchers Say

Defects in cells’ “cleaning system,” known as autophagy, may underlie nerve cell degeneration in early stages of Huntington’s disease, according to a recent study.

Treatments to improve this process in affected nerve cells could be a promising therapy for Huntington’s and other neurodegenerative diseases.

The study, “Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation,” was published in the journal Cell Reports.

Several neurodegenerative diseases, including Huntington’s, Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS), are so-called proteinopathies, named after their characteristic deposits of malformed proteins in the brain.

Nerve cells seem particularly sensitive to the buildup of these clumps, which disturb their functioning and can trigger their death.

Healthy nerve cells rely on an efficient protein quality control system that ensures rapid removal of toxic protein aggregates. Typically, cells use autophagy to do this.

Autophagy clears toxic or damaged products, or foreign invaders such as infectious agents, from within cells. The process is also important for balancing protein levels, enabling cells to selectively degrade certain proteins.

Neurodegenerative diseases have been linked with impairments in autophagy. But not much is known about the underlying molecular mechanisms through which protein clumps lead to autophagy impairments and neurodegeneration and why specific neuron subtypes are lost.

Researchers at Sweden’s Lund University  used laboratory-grown cells, mouse models and postmortem samples from Huntington’s patients to understand the role autophagy plays.

The presence of clumps of mutated huntingtin protein, a hallmark of Huntington’s disease, led to the accumulation of another protein called argonaute-2 (AGO2) inside striatal nerve cells — those primarily affected in Huntington’s — due to defects in autophagy.

In healthy cells, autophagy helps degrade AGO2. In Huntington’s nerve cells, autophagy no longer destroys AGO2 as it should, resulting in accumulation of the protein.

Because AGO2 plays a role in the formation and activity of microRNAs (miRNAs) — genetic messengers that control the conversion of gene-encoded information into proteins — its abnormal buildup results in an allover increase in miRNA levels and abnormalities in gene expression. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

Several hundred miRNAs are expressed in the brain and thought to regulate the expression of thousands of genes. “Therefore, any alteration in the miRNA network is likely to have a significant effect on neuronal function,” researchers said.

They suggest that changes in miRNA levels are an early feature of Huntington’s that lies downstream of alterations in autophagy.

Reactivating autophagy in a Huntington’s mouse model helped rescue nerve cells from AGO2 accumulation, supporting the potential of this process for therapeutic development.

“Our data also provide further support for developing autophagy-activating therapeutic approaches for [Huntington’s] and other [neurodegenerative diseases] because they suggest that activation of autophagy will not only clear toxic protein aggregates, but also directly restore dysfunctional post-transcriptional gene regulation,” they said.