Objective: To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD. Methods: Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein. Results: Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation. Conclusions: The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage. Classification of evidence: 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.

Human 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.