Sensory neuropathy and nociception in rodent models of Parkinson's disease

Abstract

Parkinson's disease (PD) often manifests with prodromal pain and sensory losses whose etiologies are not well understood. Multiple genetic and toxicity-based rodent models of PD partly recapitulate the histopathology and motor function deficits. Although far less studied, there is some evidence that rodents, similar to humans, develop sensory manifestations of the disease, which may precede motor disturbances and help to elucidate the underlying mechanisms of PD-associated pain at the molecular and neuron circuit levels. The present Review summarizes nociception and other sensory functions in frequently used rodent PD models within the context of the complex phenotypes. In terms of mechanisms, it appears that the acute loss of dopaminergic neurons in systemic toxicity models (MPTP, rotenone) primarily causes nociceptive hyperexcitability, presumably owing to a loss of inhibitory control, whereas genetic models primarily result in a progressive loss of heat perception, reflecting sensory fiber neuropathies. At the molecular level, neither α-synuclein deposits alone nor failure of mitophagy alone appear to be strong enough to result in axonal or synaptic pathology of nociceptive neurons that manifest at the behavioral level, and peripheral sensory loss may mask central 'pain' in behavioral tests. Hence, allostatic combinations or additional challenges and novel behavioral assessments are needed to better evaluate PD-associated sensory neuropathies and pain in rodents.

Keywords: Mitogenesis; Mitophagy; Non-motor Parkinson's disease; Pain; Protein aggregate; Sensory neuropathy; Synuclein.

Fig. 1.

Molecular functions of Parkinson's disease (PD) genes in rodents. The pathoetiology of PD is characterized by disruption of mitochondrial integrity and protein allostasis, the latter owing to malfunctioning of the ubiquitin-proteasome system (UPS; Box 1) and of autophagy-mediated degradation pathways. Depending on the genetic cause, a combination of redox stress, energy shortage, protein aggregates and mitochondrial-DNA-evoked inflammation sets off a progressive accumulation of cellular waste ultimately resulting in cell death that manifests in a loss of vulnerable DAergic and sensory neurons. Mutations in α-synuclein (SNCA; encoded by Park1) or overexpression of wild-type SNCA disrupt the endoplasmic reticulum (ER)-to-Golgi transport by interfering with vesicle tethering and/or fusion. Similar events may disrupt synaptic vesicle release. SNCA is a constitutively unfolded protein and the mutant is prone to aggregation. It recruits other proteins to the aggregates and may overwhelm the aggresomes and ubiquitylated cargo proteins, all requiring functional E3 ubiquitin ligases including Parkin. Mutations in Parkin, UCHL1 and SNCA all interfere with the UPS, which may result in ER-stress responses leading to secondary inhibition of translation. Proteasome dysfunctions normally elicit alternative rescue mechanisms, including activation of chaperone-mediated autophagy (CMA), in which long-lived cytosolic proteins transfer to the lysosome via the LAMP2a receptor. However, mutant SNCA or gain-of-function mutants of LRRK2 cause CMA dysfunction. Mutant LRRK2 also contributes to mitochondrial pathology and increases mitophagy. The latter requires ubiquitylation of damaged mitochondria via Pink1/Parkin, in that depolarized mitochondria expose Pink1 on the outer membrane. Pink1 then recruits Parkin, which ubiquitylates outer-membrane proteins of the damaged mitochondrial fragment for autophagy-receptor-guided engulfment and mitophagy. LKKR2 is also a regulator of mitochondrial fission/fusion. Excessive fission is associated with mitochondrial dysfunction and increased ROS production. DJ-1 acts as a redox sensor and antioxidant in mitochondria, and helps to maintain energetic and redox homeostasis. Additional mutations associated with sporadic PD affect lysosomal enzymes, including glucosylceramidase β (GBA1) (Beavan et al., 2015; Murphy and Halliday, 2014; Robak et al., 2017), α-galactosidase A (GLA) (Alcalay et al., 2018; Wise et al., 2018; Wu et al., 2008), sphingomyelin phosphodiesterase 1 (SMPD1) (Wu et al., 2014) and Niemann Pick disease type 1 (NPC1). They all associate with lysosomal storage diseases, hence showing the genetic convergence of PD and lysosomal storage disorders and the importance of lysosomal pathways. Within the nucleus, white boxes show recessive PD genes, red boxes show dominant PD genes and gray boxes show PD-associated genes.

Fig. 2.

Nociception and olfaction in PD. Sensory processing of nociception involves primary nociceptive neurons in the dorsal root ganglia (DRG), secondary projection neurons in the dorsal horn of the spinal cord, the dorsolateral thalamus and somatosensory cortex (SSC, S1). This direct path connects to the prefrontal cortex (PFC), the insula cortex and the limbic system – amygdala (Amyg), anterior cingulate cortex (ACC), nucleus accumbens (NAc), areas of the midbrain [e.g. ventral tegmental area (VTA); periaqueductal gray (PAG)] and hippocampus. These areas process the cognitive and affective modulation of ‘pain’ and are needed to feel the reward associated with pain relief. This pain-relief reward is based on the release of DA in the NAc from VTA afferents and is strengthened by endocannabinoids. In addition, DAergic pain-inhibiting pathways arise from the midbrain and signal to the dorsal horn of the spinal cord. Although VTA neurons are less vulnerable to genetic causes or toxins than DA neurons of the substantia nigra, dysfunctions in these reward and pain-inhibitory pathways likely contribute to PD-associated pain. Sensory neurons are particularly vulnerable to defects of the ubiquitin-proteasome system (UPS), loss of mitochondria and inflammation, which result in axonal damage and loss of terminal nerve fiber endings. Clinically, fiber loss manifests as small-fiber or mixed-fiber sensory neuropathies, with sensory losses and pain. Rodent models of PD more or less recapitulate the sensory loss of smell, taste and nociception, which may precede motor-function deficits. Prodromal pain and olfactory deficits are highly prevalent, the latter resulting from degenerations of olfactory sensory neurons. SNCA deposits in the olfactory bulb spread to the projections to the olfactory cortex and areas involved in regulation of social behavior, nutrition and hormonal balances. AOB, accessory olfactory bulb; ARC, arcuate nucleus; CGRP, calcitonin-related peptide; eCBs, endocannabinoids; LC, locus coeruleus; MOB, main olfactory bulb; NA, noradrenaline; 5HT, serotonin; OT, olfactory tract; Piri, piriform cortex; SNr, substantia nigra; SP, substance P; Thal, thalamus; VNO, vomeronasal organ.