Myo-inositol concentration in the medial prefrontal cortex is associated with changes in brain white matter microstructure in early psychosis.

Amyotrophic lateral sclerosis (ALS) is a disease characterized by muscle atrophy due to the degeneration of neurons in the cortex, brainstem and spinal cord (; ; ). The disease starts with mild symptoms such as weakness, difficulty swallowing and slurred speech, but quickly progresses to more severe symptoms such as motor dysfunction, laboured breathing and paralysis. Death typically occurs due to respiratory failure within 3-5 years of diagnosis (; ; ). Ninety percent of ALS cases are sporadic ALS with no identified family history, whereas the remaining 10% are classified as familial ALS, involving one or more affected family members (; ). More than 30 loci contributing to distinct or overlapping pathomechanisms – such as oxidative stress, neuroinflammation, lipid dysregulation, mitochondrial dysfunction and proteostasis failure – have been associated with ALS, indicating the multifactorial and complex nature of the disease (; ; ; ; ). Although ALS was first described almost a century ago, little has been achieved in terms of treatment, with very few available drugs, offering only modest benefits (; ; ). Additionally, owing to its oligogenic nature, the molecular mechanism(s) underlying ALS remains poorly understood, rendering the disease largely untreatable. Thus, efforts to investigate molecular mechanisms and gene networks underlying ALS in model organisms can pave the way for the development of more effective therapies. The eighth ALS locus to be identified was vesicle-associated membrane protein (VAMP) associated protein B (). A dominant proline-to-serine point mutation at position 56 (P56S) in the major sperm protein (MSP) domain was identified in Portuguese-Brazilian families and is associated with familial ALS (). is a definitive ALS locus (; ). It encodes a single-pass type IV integral membrane protein that resides on the endoplasmic reticulum (ER) membrane. VAPB has three domains: the C-terminal transmembrane domain, which is inserted into the ER membrane; a coiled-coil domain that helps form multimers; and the N-terminal MSP domain, which faces the cytosol (; ; ). The MSP domain can interact with a wide range of partner proteins that decorate the surface of organelle membranes and facilitate the formation of the membrane-membrane contact site (MCS) between the ER and these (other) organelles. VAPB, through the MCS, plays a crucial role in efficiently coordinating inter-organelle processes, thereby maintaining cellular homeostasis. These cellular processes include membrane trafficking, lipid transport and lipid homeostasis, immune signalling, calcium signalling, autophagy, stress response and protein homeostasis (reviewed in ; ; ; ; ; ). Modulation and disruption of VAP-related MCSs can affect these functions, in whole or in part (; ; ).