Mechanism Of Presenilin 1 Regulating The Structural Function Of MAM Regions And The Survival Of Neurons Through The PARL-PINK1-PARKIN Pathway

Presenilin(PS)gene mutation,including Presenilin 1(PS1)and 2(PS2)Presenilin mutation is the leading cause of the Familial Alzheimer’s disease(FAD),a neurodegenerative disease.This is the so-called “gain of Presenilin function” etiological mechanism.It is important for synapse generation,neuron differentiation,modulating calcium ions as well as neurotransmitters,and maintaining the cell homeostasis.PS1 interference or knockdown,namely “PS1 dysfunction”,is one of the important etiological mechanisms of FAD.In previous studies,we found that PS1 dysfunction could activate the apoptosis signal of the PS1-PARL-OPA1 mitochondria,while inducing a mild stress of the endoplasmic reticulum(ER)could effectively improve the neuronal apoptosis resulting from this.Also,the contact part of mitochondria and ER,namely the mitochondria-associated ER membrane(MAM),will change its structure and functions in the absence of PS1 function.The MAM region plays an important role in maintaining intracellular environment homeostasis and cellular metabolic activities(e.g.calcium homeostasis,cholesterol and phospholipid metabolism,mitochondrial functions,etc.).On the basis of previous research results,we explore the molecular mechanism that regulates the structural and functional changes of MAM under two conditions,PS1 deficiency only as well as PS1 deficiency accompanied by a mild ER stress.By a variety of techniques,it was found that PS1 deficiency affects the structural function of MAM region through the PARL-PINK1-PARKIN pathway.Moreover,MAM damage can be recovered when a mild ER stress is induced in ps1-deficient cells,and this is related to the function of PARL-PINK1-PARKIN.However,a severe ER stress is not able to restore the function of MAM.Hence,in the case of cell damage and homeostasis destruction,MAM may be an important regulatory site for cell recovery.This study has preliminarily explored the way that PS1 regulates MAM,which plays an important role in protecting the structure and function of the MAM region and maintaining the cell homeostasis as well as its normal physiological and biochemical reactions.Based on this,it is expected to further and more completely elucidate the molecular basis of PS1 gene regulating the fate of nerve cells(survival or apoptosis).It provides a new idea for the treatment of neurodegenerative diseases related to PS1 deficiency and MAM area injury.