Alpha-synuclein Toxicity in the Early Secretory Pathway: How It Drives Neurodegeneration in Parkinsons Disease

نویسندگان

  • Ting Wang
  • Jesse C. Hay
چکیده

Alpha-synuclein is a predominant player in the pathogenesis of Parkinson's Disease. However, despite extensive study for two decades, its physiological and pathological mechanisms remain poorly understood. Alpha-synuclein forms a perplexing web of interactions with lipids, trafficking machinery, and other regulatory factors. One emerging consensus is that synaptic vesicles are likely the functional site for alpha-synuclein, where it appears to facilitate vesicle docking and fusion. On the other hand, the dysfunctions of alpha-synuclein are more dispersed and numerous; when mutated or over-expressed, alpha-synuclein affects several membrane trafficking and stress pathways, including exocytosis, ER-to-Golgi transport, ER stress, Golgi homeostasis, endocytosis, autophagy, oxidative stress, and others. Here we examine recent developments in alpha-synuclein's toxicity in the early secretory pathway placed in the context of emerging themes from other affected pathways to help illuminate its underlying pathogenic mechanisms in neurodegeneration.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Clioquinol-induced ordered conformational behavior in alpha-synuclein: promising relevance for therapeutic approach to Parkinson's disease

Parkinson?¦s disease (PD) is a devastating and an intricate complex neurological disorder that results from the progressive degeneration of nerve cells in Substantia nigra that controls movement. The pathological hallmark of PD is the formation of insoluble protein aggregates known as lewey bodies. Alpha-synuclein is the major constituent of these fibrillar structures. Alpha-synuclein a 140 ami...

متن کامل

Clioquinol-induced ordered conformational behavior in alpha-synuclein: promising relevance for therapeutic approach to Parkinson's disease

Parkinson?¦s disease (PD) is a devastating and an intricate complex neurological disorder that results from the progressive degeneration of nerve cells in Substantia nigra that controls movement. The pathological hallmark of PD is the formation of insoluble protein aggregates known as lewey bodies. Alpha-synuclein is the major constituent of these fibrillar structures. Alpha-synuclein a 140 ami...

متن کامل

α-Synuclein Delays Endoplasmic Reticulum (ER)-to-Golgi Transport in Mammalian Cells by Antagonizing ER/Golgi SNAREs

Toxicity of human alpha-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elemen...

متن کامل

The exploration of rotenone as a toxin for inducing Parkinson's disease in rats, for application in BBB transport and PK-PD experiments.

INTRODUCTION In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat. METHODS Studies were performed using Male Lewis rats...

متن کامل

Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson's disease.

Phosphorylation is involved in numerous neurodegenerative diseases. In particular, alpha-synuclein is extensively phosphorylated in aggregates in patients suffering from synucleinopathies. However, the share of this modification in the events that lead to the conversion of alpha-synuclein to aggregated toxic species needed to be clarified. The rat model that we developed through rAAV2/6-mediate...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 9  شماره 

صفحات  -

تاریخ انتشار 2015