[대학원 생명과학과 세미나 안내] 

연사 : 장재락 교수(아주대학교 의과대학)

연제 : Dysregulation of ER shaping and autophagy in neurological disorders

일시 : 2017년 4월 7일 (금) 오후 4시 

장소 : 하나과학관 A동 109호

초청교수 : 조용철 교수

Abstract

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurological disorders with the cardinal feature of a length-dependent axonopathy of corticospinal motor neurons, resulting in lower-extremity spasticity and weakness. HSPs have traditionally been divided into categories referred to as pure or complex, based upon the presence (complex) or absence (pure) of additional clinical features. More recently, a genetic classification scheme has predominated, with HSPs identified by their spastic gait (SPG) genetic loci in order of identification, SPG1–SPG77. To date, well over 50 genes have been identified, encompassing autosomal dominant, autosomal recessive, X-linked, and maternal inheritances, with de novo mutations also described. Despite this broad genetic heterogeneity, several common cellular mechanistic themes have emerged.
In the first part of the presentation, I will show the pathogenesis of HSP caused by an alteration in endoplasmic reticulum (ER) structure. Over half of hereditary spastic paraplegia cases are caused by pathogenic mutations in four genes encoding proteins that function in tubular ER network formation: atlastin-1 (SPG3A), spastin (SPG4), reticulon 2 (SPG12), and receptor expression-enhancing protein 1 (SPG31). SPG33 protein protrudin also contains hydrophobic, intramembrane hairpin domains that generate high curvature in ER tubules. Protrudin interacts with other tubular ER proteins implicated in the pathogenesis of HSP, and functions in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections.
Next, I will show the pathogenic link between HSP and autophagy. Autosomal recessive HSP with thin corpus callosum (AR-HSP-TCC) is a common subtype of complex HSP; SPG11 and SPG15 are the two most prevalent autosomal recessive HSPs (AR-HSPs), comprising about 70% of AR-HSP-TCC. Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. I will show how the mutations in SPG11 and SPG15 impair lysosome biogenesis and autophagy.