Neurodegenerative diseases like Alzheimer's (AD), Parkinson's (PD), and ALS have distinct symptoms but share a core pathology: the buildup of misfolded, aggregated proteins in the central nervous system (CNS).

This buildup results from a failure in the brain's protein quality control (PQC) systems.

What was once thought to be a passive consequence of aging is now recognized as a highly regulated biological process gone awry. At the center of this disruption are enzymes that govern proteostasis, particularly those involved in the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathways.

The Machinery of Proteostasis: Key Enzymes and Mechanisms

Proteostasis encompasses all cellular pathways that control the biogenesis, folding, trafficking, and degradation of proteins. In neurons—which are post-mitotic and have limited regenerative capacity—precision in protein regulation is critical. The UPS and autophagy are two primary degradation systems.

A pivotal enzyme in this process is valosin-containing protein (VCP/p97), an AAA+ ATPase that extracts misfolded proteins from cellular compartments such as the endoplasmic reticulum (ER), targeting them for degradation. Mutations in the VCP gene have been associated with multisystem proteinopathy (MSP), which includes inclusion body myopathy, Paget disease of bones, and frontotemporal dementia.

These mutations interfere with substrate recognition and processing, leading to toxic protein retention and neuronal death.

Another emerging player is UBE2O, a hybrid E2/E3 enzyme. Unlike conventional E2 enzymes, UBE2O independently ubiquitinates substrates and has been found to be elevated in stress responses within the CNS. A study published in Nature Neuroscience in 2024 identified that UBE2O over-expression in transgenic tauopathy mice reduced tau phosphorylation and ameliorated synaptic deficits, suggesting its protective role against neurodegeneration.

Mitochondrial Quality Control and Enzyme Interaction

Mitochondrial dysfunction is a hallmark of multiple neurodegenerative diseases. The integrity of mitochondria is heavily influenced by enzymes that regulate mitochondria-associated degradation (MAD) and mitophagy. VCP interacts with cofactors Npl4 and Ufd1, facilitating the extraction and disposal of damaged mitochondrial proteins. Impaired VCP function disrupts this process, resulting in energy deficits and increased oxidative stress—both of which are neurotoxic.

In Parkinson's disease, mutations in PINK1 and Parkin, two enzymes that coordinate mitophagy, lead to the accumulation of defective mitochondria. This not only impairs ATP production but also initiates inflammatory cascades. Emerging therapies are exploring ways to modulate these enzymes to restore mitochondrial function and halt disease progression.

Deubiquitinating Enzymes: A Double-Edged Sword

While ubiquitination tags proteins for degradation, deubiquitinating enzymes (DUBs) such as USP14 and UCHL1 remove these tags, potentially delaying degradation. Dysregulation of DUBs in aging brains leads to accumulation of ubiquitin-positive inclusions, as seen in Lewy bodies in PD and neurofibrillary tangles in AD.

Experimental inhibition of USP14 has shown to enhance proteasomal degradation in preclinical models. However, because DUBs also regulate vital signaling cascades, therapeutic modulation requires highly selective inhibitors to avoid unwanted systemic effects.

Inflammation, Enzyme Dysfunction, and Protein Toxicity

The failure of enzymatic PQC systems is further compounded by neuroinflammation. Microglia, the resident immune cells in the brain, respond to protein aggregates by releasing pro-inflammatory cytokines. This exacerbates neuronal stress and may further impair enzyme activity. In ALS, for instance, inflammatory mediators like TNF-α and IL-1β suppress the expression of key UPS-related enzymes, creating a vicious cycle of inflammation and proteotoxicity.

Additionally, recent findings from the German Center for Neurodegenerative Diseases (DZNE) highlight how proteasomal overload, caused by impaired clearance of misfolded proteins, shifts the cellular environment toward chronic inflammation and cellular senescence—both detrimental to neuronal survival.

Emerging Therapeutics: Precision Targeting of Enzymatic Pathways

Next-generation therapeutics are focusing on upstream correction rather than downstream damage control. One promising area is small molecule VCP inhibitors (such as CB-5083), which enhance autophagic flux but have encountered issues with retinal toxicity in early trials. Alternatively, RNA-based therapies are being investigated to modulate enzyme expression with high specificity.

Gene editing tools such as CRISPR-Cas9 are being adapted to correct disease-causing mutations in enzyme-encoding genes. For example, experimental editing of mutant VCP alleles in induced pluripotent stem cell-derived neurons showed normalized protein turnover and improved cellular resilience to stress.

Neurobiologist Dr. Alina Forstner of the University of Zurich emphasizes, "We must stop thinking of enzymes as background actors. They're molecular decision-makers with the power to determine the life or death of a neuron."

The recognition of enzymes as central to protein quality regulation has revolutionized the approach to neurodegenerative diseases. Their roles transcend mere catalysis—they dictate cellular integrity, inflammatory thresholds, and stress response dynamics.

As enzyme-targeted interventions progress from the bench to clinical trials, they may well usher in a new era of etiology-specific and mechanism-driven therapeutics. The future of neurodegeneration treatment may not lie in dissolving aggregates—but in preventing them through precision enzymology.