This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

SummaryHuman autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.

(1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD.

Our study reveals a loss of retinal nerve fibers in the temporal quadrant in PD, which is typically susceptible in mitochondrial optic neuropathies.