Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.

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.

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