Vacuolar Protein Sorting 35 (VPS35) is a protein found within cells throughout the body, playing a significant role in various cellular processes. Scientists are actively investigating VPS35 because its proper function is connected to overall cellular health, and disruptions in its activity have been observed in several complex conditions. This protein is a subject of growing scientific interest.
What VPS35 Does in Cells
VPS35 is a component of the “retromer complex,” a group of proteins that sorts and recycles cellular materials. This complex acts like a cellular postal service, ensuring that proteins and other components are delivered to their correct destinations, preventing misrouting or degradation. It facilitates the transport of membrane proteins from endosomes back to the trans-Golgi network or cell surface, preventing their degradation in lysosomes.
VPS35, as a central subunit, helps maintain lysosome health, which are the cell’s recycling and waste disposal centers. Impaired VPS35 function can lead to problems with this recycling system, causing an accumulation of dysfunctional proteins. VPS35 also influences mitochondrial function by regulating the transport of proteins essential for mitochondrial health.
VPS35 and Brain Health
VPS35’s role in protein trafficking and waste removal is particularly important for neurons in the brain. Neurons are highly active cells that rely on efficient internal transport and waste management to maintain their complex structures and functions. Proper VPS35 activity helps ensure the correct distribution of neurotransmitter receptors, such as AMPA and NMDA receptors, at synaptic sites, which is fundamental for communication between neurons.
VPS35 also maintains mitochondrial health within neurons, which are the cell’s energy producers. Dysfunction of VPS35 can lead to mitochondrial fragmentation, impairing normal mitochondrial function and impacting neuronal survival. It is also involved in regulating synaptic structure and function by influencing the transport of proteins associated with synapse formation and plasticity.
When VPS35 Goes Wrong: Disease Connections
When VPS35 does not function correctly, it can contribute to several neurodegenerative diseases. A strong genetic link exists between VPS35 gene mutations and Parkinson’s disease, specifically the Asp620Asn (D620N) missense mutation. This mutation is associated with late-onset, autosomal dominant familial Parkinson’s disease, with individuals often experiencing symptoms similar to sporadic Parkinson’s disease. The D620N mutation is thought to impair the retromer complex’s ability to sort and recycle proteins, leading to the accumulation of harmful proteins like alpha-synuclein within neurons.
Reduced VPS35 levels or dysfunction have also been observed in other neurodegenerative conditions, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). In Alzheimer’s disease, VPS35 deficiencies are linked to increased levels of amyloid-beta (Aβ) peptides, a hallmark of the disease, due to abnormal processing of amyloid precursor protein (APP). Impaired VPS35 function can also affect autophagy, the cell’s self-cleaning process, leading to the buildup of protein aggregates and damaged cellular components.
Investigating VPS35 for Medical Insights
Research is focused on understanding VPS35 dysfunction to gain deeper insights into neurodegenerative diseases. Scientists are exploring the specific pathways influenced by VPS35 and how mutations, such as the D620N variant, disrupt its normal operations. This research includes examining how VPS35 affects processes like mitochondrial maintenance, lysosomal degradation, and the trafficking of specific proteins, all implicated in disease progression.
Investigators are also exploring VPS35 as a potential target for developing new strategies to prevent or slow the progression of these diseases. Research is underway to identify compounds that could activate or supplement VPS35 activity, potentially promoting the clearance of harmful protein aggregates like amyloid-beta plaques. While no specific therapies are currently available, these ongoing studies aim to uncover mechanisms that could lead to future treatments or biomarkers for assessing neurodegeneration risk.