Cholestenoic acids regulate motor neuron survival via liver X receptors.

Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3ß,7α-dihydroxycholest-5-en-26-oic acid (3ß,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3ß-hydroxy-7-oxocholest-5-en-26-oic acid (3ßH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3ß,7α-diHCA and 3ßH,7O-CA, 3ß-hydroxycholest-5-en-26-oic acid (3ß-HCA) caused motor neuron cell loss in mice. Mutations in CYP7B1 or CYP27A1, which encode enzymes involved in cholestenoic acid metabolism, result in different neurological diseases, hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), respectively. SPG5 is characterized by spastic paresis, and similar symptoms may occur in CTX. Analysis of CSF and plasma from patients with SPG5 revealed an excess of the toxic LXR ligand, 3ß-HCA, while patients with CTX and SPG5 exhibited low levels of the survival-promoting LXR ligand 3ß,7α-diHCA. Moreover, 3ß,7α-diHCA prevented the loss of motor neurons induced by 3ß-HCA in the developing mouse midbrain in vivo.Our results indicate that specific cholestenoic acids selectively work on motor neurons, via LXR, to regulate the balance between survival and death.

A novel presenilin1 mutation (Q223R) associated with early onset Alzheimer's disease, dysarthria and spastic paraparesis and decreased Abeta levels in CSF.

BACKGROUND AND PURPOSE: A novel presenilin1 (PSEN1) mutation associated with dementia and spastic paraplegia in a family with five affected individuals is described. The index patient was a 35-year-old man presenting with cognitive decline, behavioural symptoms, dysarthria, and gait disorder due to spasticity. METHODS AND RESULTS: Genetic analysis revealed a missense mutation Gln223Arg in exon 7. Initial CSF analysis revealed drastically decreased Abeta42 level despite marginally decreased FDG metabolism. CONCLUSION: Cerebrospinal fluid biomarker analysis might point towards genetic analysis of PSEN1 in patients with positive family history and age of onset below 60 years.

Acquired progressive spastic paraparesis due to neurobrucellosis: a case report.

A 39-year-old man with a 4-month history of transient pins and needles sensations occurring below the waist while walking and difficulty walking presented to our outpatient clinic. He had an approximate 1-year history of bilateral hearing loss, the etiology of which was unknown. His symptoms had been progressive, and there was no significant family history. He demonstrated a spastic gait and required assistance for walking. Deep tendon reflexes were hypertonic; a sensation deficit was defined as originating from the 12th thoracic vertebra. Babinski's sign was positive bilaterally. Sphincter abnormalities were seen in the patient's bladder and bowel functions. Cerebral and spinal magnetic resonance images with contrast media were unremarkable. An analysis of the patient's cerebrospinal fluid was consistent with neurobrucellosis. Owing to spastic paraparesis and hearing loss, the diagnosis of neurobrucellosis was made. Combined antimicrobial therapy was started and continued 6 months. His neurologic condition improved, and he was able to walk without help after 3 months' treatment. Our case illustrates that acquired progressive spastic paraparesis may occur during the course of neurobrucellosis. Neurobrucellosis should be borne in mind when patients present with spastic paraparesis.