Initiation of Parkinson’s disease from gut to brain by δ-secretase

Abstract

Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson's disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients' gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/ Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments' fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.

The emerging role of α-synuclein truncation in aggregation and disease

“…Extending the study of prion-like seeding capacity of truncated αsyn fibrils to cellular and animal models is complicated due to additional extrinsic factors now involved such as modulation of cellular uptake and spread of fibrils due to truncation (194,195), trafficking to subcellular compartments (196), and structural changes to the truncated fibril due to additional PTMs; most of these variables have not been studied in relation to truncated αsyn fibrils or even typical αsyn seeding experiments. Nonetheless, cellular (22, 38, 91-93, 103, 120, 159, 189, 197, 198) and animal (133,159,189,199) experiments using fibrils containing truncated αsyn have shown some similar findings to in vitro studies.…”

“…Our lab has demonstrated that fibrils containing both C-truncated and FL αsyn in a 1:1 ratio seed similarly to, or slightly less than, FL αsyn fibrils suggesting that the extreme structural alterations of fibrils comprised of C-truncated αsyn are attenuated in this configuration (22,159). Additionally, fibrils comprised of truncated αsyn may interact with other neurodegenerative proteins as well, as a seed containing both 1-103 truncated αsyn and truncated tau was superiorly able to induce αsyn pathology when injected into mice compared with 1-103 or FL αsyn fibrils which were themselves about equal in prion-like potency (133).…”

“…Indeed, PD is thought to have early pathologic αsyn formation in the enteric nervous system (98), and it was observed using the appendix from PD patients that levels of truncated αsyn, particularly C-truncated at residue 125, were greatly elevated compared to the SNpc from the same patients and the appendices of controls (132). Another study found elevated levels of 103 Ctruncated αsyn in the colon of PD patients (133). Likewise, findings from our laboratory showed that C-terminal truncation may be highly prevalent in the medial temporal lobe in LBD, which is afflicted early in disease, compared to the cingulate cortex (67).…”

“…Fibrils comprised of 21-140 αsyn (91,93,97,189,198,199), 58-140 αsyn (92), and 1-89 αsyn (92) have been observed to induce FL αsyn aggregation and inclusion formation equally to FL αsyn fibrils while 1-99 αsyn fibrils showed a decrease (120). Despite the in vitro findings that 1-120 and 1-103 αsyn fibrils were excellent seeds of FL αsyn, in cellular models 1-120 αsyn was either equal to or less than FL αsyn fibrils in seeding (91,92,103,189,198) and likewise for 1-103 αsyn (133).…”

Vagus Nerve and Stomach Synucleinopathy in Parkinson’s Disease, Incidental Lewy Body Disease and Normal Elderly Subjects: Evidence Against the “Body-First” Hypothesis

“…Although we used an immunohistochemical method that has been repeatedly demonstrated to be highly sensitive and specific for both CNS and PNS -synuclein pathology, as found in multi-center blinded studies [69,70,78,88] and biochemical studies [75], it is possible that the initial form of peripheral -synuclein pathology may differ from that commonly seen in the CNS. Alternate forms may include non-phosphorylated -synuclein, truncated -synuclein [89][90][91] and -synuclein aggregates [39,92].…”