Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases

Abstract

Chronic pain, defined by persistent pain beyond normal healing time, is a pervasive and debilitating condition affecting up to 30-50% of adults globally. In parallel, neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and cognitive or motor decline, often underpinned by pathological protein misfolding and aggregation. Emerging evidence suggests a potential mechanistic link between chronic pain and NDs, with persistent pain contributing to neuroinflammatory states and protein homeostasis disturbances that mirror processes in neurodegeneration. This review explores the hypothesis that protein misfolding and aggregation serve as a mechanistic bridge between chronic pain and neurodegeneration. We systematically examine molecular pathways of protein misfolding, proteostasis dysfunction in chronic pain, and shared neuroimmune mechanisms, highlighting prion-like propagation of misfolded proteins, chronic neuroinflammation, and oxidative stress as common denominators. We further discuss evidence from experimental models and clinical studies linking chronic pain to accelerated neurodegenerative pathology-including tau accumulation, amyloid dysregulation, and microglial activation-and consider how these insights open avenues for novel therapeutics. Targeting protein aggregation, enhancing chaperone function, modulating the unfolded protein response (UPR), and attenuating glial activation are explored as potential strategies to mitigate chronic pain and possibly slow neurodegeneration. Understanding this intersection not only elucidates chronic pain's role in cognitive decline but also suggests that interventions addressing proteostasis and inflammation could yield dual benefits in pain management and neurodegenerative disease modification.

Keywords: chronic pain; endoplasmic reticulum stress; neurodegenerative diseases; neuroinflammation; protein aggregation; protein misfolding; unfolded protein response.

Figure 1

Prion-like propagation of misfolded proteins in pain and neurodegeneration. Misfolded and aggregated proteins propagate between neurons and glial cells through multiple mechanisms, resembling prion-like transmission. Pathological proteins can spread via (1) neuron-to-neuron transmission through axonal transport, (2) exosomal transfer between cells, and (3) microglial engulfment and re-release of misfolded proteins, among others. Neuroinflammation, particularly microglial activation and cytokine release, exacerbates protein propagation, contributing to neurodegeneration. Chronic pain may further accelerate this process by maintaining a prolonged inflammatory state, increasing oxidative stress, and disrupting proteostasis, ultimately amplifying misfolded protein accumulation and spread.

Figure 2

Mechanistic pathways linking chronic pain to neurodegenerative diseases. Chronic pain and neurodegenerative diseases share interconnected pathophysiological mechanisms that drive progressive neuronal dysfunction. These mechanisms are closely linked and may converge at protein misfolding and aggregation. Chronic pain can aggravate cellular stress responses, leading to proteostasis disruption and neurodegeneration, while neurodegenerative processes may increase pain sensitivity, thereby establishing a bidirectional loop.