Defect in BNIP-H causes ataxia disease
18 Sep 2015 NUS scientists identified a function of BNIP-H as a linker to transport metabolic enzyme ATP citrate lyase (ACL) on the motor protein towards the end of neurons.
Neuronal cells in human brain require neurotransmitters to communicate with each other. Acetylcholine is the first neurotransmitter discovered in 1936 which controls learning, memory, cognition and muscle contraction. Despite having good understanding that the synthesis and release of acetylcholine require multiple enzymes to work together, essentially little is known about how, where and when the biochemical function of this “enzymatic machinery” is controlled. BNIP-H mutation has been linked to human ataxia disease (a form of muscle movement disorder).
A team led by Prof LOW Boon Chuan from the Department of Biological Sciences in NUS together with the University of Michigan, Ann Arbor, USA has identified an essential function of BNIP-H as a scaffold or linker to transport the key metabolic enzyme ACL on the motor protein towards the end of neurons. By doing so, BNIP-H defines the precise localisation, duration and strength of acetylcholine signaling that determines the growth of neurons and the coordination of body movements. This finding resolved a longstanding puzzle that how the secretion of chemical is regulated by proper localization of its synthesizing enzyme.
Despite the evidences that BNIP-H mutant is linked to ataxia and dystonia in several animal models, the molecular mechanism on how BNIP-H defect causes motor disorder is still unclear. The novelty of the finding is that they identified an important mechanism on regulating the localization of metabolic enzymes for neurotransmitter (acetylcholine) synthesis. This finding further highlights the significance of understanding the precise spatiotemporal regulation of metabolic enzymes in cellular and developmental processes, a subject that clearly requires more effort to explore and to exploit for therapeutics intervention.
This work encompasses integrative approaches to understand acetylcholine signaling, including using primary and cultured neurons from rodent and zebrafish models, molecular genetics, protein biochemistry and high speed live imaging. They also establish the first ACL-based ataxia model in the zebrafish that recapitulates the ataxic phenotype seen in human patients. These findings provide the first detailed understanding at the molecular, cellular and organism levels on how defect in ACL trafficking impairs cholinergic signaling that leads to the development of ataxia (see Figure).
As the synthesis and secretion of neurotransmitter could be regulated by the localization of metabolic enzyme, their finding could provide new direction to better understand causes of cholinergic related diseases, such as Alzheimer’s disease, Down’s syndrome, ataxia and schizophrenia. Changing the activity of BNIP-H or/and its downstream effectors might be used to treat those diseases caused by dysregulation of cholinergic neurotransmission. This finding will prompt more research effort into this area. Next, they are going to examine whether BNIP-H regulates the activity of synaptic vesicles for neurotransmission.
Figure shows that BNIP-H transports the metabolic enzyme ACL along the microtubules to neurite terminals. At neurite terminals, BNIP-H and ACL recruits another metabolic enzyme ChAT for acetylcholine synthesis and release. The secreted acetylcholine feedbacks to promote neurite outgrowth. [Image credit: the Mechanobiology Institute Singapore, MBI]
Sun JC, Pan CQ, Chew TW, Liang FY, Burmeister M, Low BC. “BNIP-H recruits the cholinergic machinery to neurite terminals to promote acetylcholine signalling and neuritogenesis.” Developmental Cell (2015) 34(5) 555.