课程大纲

COURSE SYLLABUS

课程代码/名称

Course Code/Title

蛋白质折叠错误与神经退行性疾病

Protein misfolding and neurodegenerative diseases

课程性质

Compulsory/Elective

专业选修课 / Elective

开课单位

Offering Dept.

医学院生化系/ Department of Biochemistry, School of Medicine

课程学分/学时

Course Credit/Hours

3/48

授课语言

Teaching Language

英文 / English

授课教师

Instructor(s)

苏明媛 / Ming-Yuan Su

开课学期

Semester

2022 秋 /2022 Autumn

是否面向本科生开放

Open to undergraduates

or not

否 / No

先修要求

Pre-requisites

（如面向本科生开放，请注明区分内容。 If the course is open to undergraduates, please

indicate the difference.）

10.

教学目标

Course Objectives

（如面向本科生开放，请注明区分内容。 If the course is open to undergraduates, please indicate the difference.）

This course aims to introduce students the information on protein properties, protein quality control

systems, chaperone assisted folding and protein conformational diseases in neuron and beyond. In

particular, the students will gain familiarity with principles of protein misfolding; protein misfolding

diseases as well as current therapies.

The student can improve their abilities listed below:

 understand the fundamental properties of protein.

 describe protein folding kinetics and aggregate formation.

 understand and describe the biophysical and biochemical techniques to study protein folding and

aggregates.

 be able to evaluate and interpret the scientific publications in the field.

 describe fibril structure and biophysical properties and become familiar with the relationship

between protein misfolding and neurodegenerative as well as other diseases.

 become able to search, read, critically evaluate and discuss scientific literature related to protein

misfolding and human diseases.

11.

教学方法

Teaching Methods

（如面向本科生开放，请注明区分内容。 If the course is open to undergraduates, please indicate the difference.）

Lecture, discussion and presentation.

12.

教学内容

Course Contents

（如面向本科生开放，请注明区分内容。 If the course is open to undergraduates, please indicate the difference.）

Section 1

1. Fundamental properties of protein

In this section, we will cover the basic structure and function of

proteins, including biochemical properties of amino acids, ribosomes

structure and function, translation in eukaryotes and peptide bond

formation. I will also teach co-translational and post-translational protein

targeting and translocation.

Section 2

2. Protein folding and three-dimensional structure

This section will introduce non-covalent interactions in proteins,

including ionic interactions, hydrogen bonds, Van der Waals forces and

hydrophobic interactions. I will introduce the concepts of the entropy and

hydrophobic effect in protein folding, the energy landscape and folding

funnel. We will discuss different levels of protein structures from primary

to quaternary structures.

Section 3

3. Molecular chaperones and catalysts of protein folding

In this section, we will learn molecular chaperones and catalysts of

protein folding including Hsp60 family chaperonins encapsulate proteins

in folding cages, Hsp70 chaperones maintain cellular proteostasis, Hsp90

chaperones stabilize proteins and molecular chaperones handle misfolded,

intrinsically disordered and amyloidogenic proteins. We will also learn

disulfide bond formation proteins, peptidyl-prolyl cis/trans isomerases and

heat shock response.

Section 4

4. Protein misfolding and aggregation

In this section, we will talk about protein misfolding caused by

dominant-negative mutations, changes in environmental conditions (pH,

ionic strength, temperature, and protein concentrations), error in post-

translational modifications, increase degradation rate, oxidative stress and

error in trafficking etc.

Section 5

5. Technique in study protein folding and protein aggregation

This section will introduce different technique to study protein folding

and protein aggregates, including single molecular biophysics (atomic

force microscopy, optical tweezers, pulling forces), fluorescent dyes for

protein aggregates detection, as well as the structural approaches and

principles of cryoEM or cryoET etc.

Section 6

6. Protein quality control system- autophagy

The section will introduce cellular mechanism of autophagy, a pathway

to dispose misfolded and aggregated protein or damages organelles. We

will cover the topics including formation of phagophore, substrate binding

and autophagosome formation, current strategies for targeting autophagy

for disease treatment. We will also talk about endoplasmic reticulum

associated degradation and the unfolded protein response.

Section 7

7. Protein quality control system-protease and ubiquitin proteasome

systems

In this section, we will cover protein machinery that remove unfolded

or aggregated proteins including Lon protease, ClpX protease and

VCP/p97 protease etc. We will also introduce another important protein

quality control pathway ubiquitin proteasome systems that aid protein

degradation and turnover, and how the ubiquitination tagged protein are

degraded by proteasome.

Section 8

8. Mid-term exam

Section 9

9. Neuron, synapse and neurotransmission

In this section, we will cover the structure and function of neurons, the

synapse and neurotransmission, ions channels.

Section 10

10. Alzheimer’s disease (AD)

This section will cover neurodegenerative disease related to protein

misfolding- Alzheimer’s disease. We will talk about the pathogenesis for

AD, APP processing and amyloid beta peptide, inflammation and

tauopathies etc.

Section 11

11. Parkinson’s disease (PD)

In this section, we will learn the structural characteristics of human

alpha-synuclein, conformational behaviour of wild type and PD-related

synucleins, their aggregations and mechanism of cell to cell spread.

Section 12

12. Huntington’s disease and Prion disease

This section will talk about Huntington’s disease and Prion disease,

focusing on the structure of huntingtin protein, polyQ repeats and how

does it misfold, oligomerize and aggregate. The student will also learn the

prion biology and diseases, prion protein and structure, transmission and

bovine spongiform encephalopathy etc.

Section 13

13. Amyotrophic lateral sclerosis and Frontotemporal degeneration

(ALS/FTD)

In this section, we will cover the mutations in the SOD1 gene cause

amyotrophic lateral sclerosis, the gain of toxic function by mutant SOD1,

mutations in TDP-43 and FUS gene cause ALS/FTD, gain and loss of

function of C9orf72 gene mutation in ALS/FTD, G4C2 repeats generate G-

quadruplexes, repeated associated non-ATG (RAN) translation generates

toxic proteins and RNAs.

Section 14

14. Cystic fibrosis, alpha-1 antitrypsin deficiency and cataract as

protein-aggregation diseases

This section will introduce three different type of diseases caused by

protein aggregation and their mechanism leads to diseases. Cystic fibrosis

caused by mutations in the CFTR gene leading to misfolding and other

defects, alpha-1 antitrypsin deficiency by point mutation leads to

accumulation of misfolded secretory glycoprotein in the endoplasmic

reticulum. Cataract caused by aggregation of crystallin protein.

Section 15

15. Diagnosis and therapeutic strategies targeting protein aggregates

In this section, the students will learn current and emerging strategies

to ameliorate aggregation-associated degenerative disorders, with a focus

on disease-modifying strategies that prevent the formation of and/or

eliminate protein aggregates, such as antisense oligonucleotides (ASO),

antibody mediated protein aggregate clearance, inhibition of Aβ levels by

secretase inhibition.

Section 16

16. Final presentation

A list of scientific publications related to the topic of the course will

be provided in the section 10 of the lectures. Each student will select one to

present and discuss for 30 mins.

13.

课程考核

Course Assessment

（

○

考核形式 Form of examination；

○

.分数构成 grading policy；

○

如面向本科生开放，请注明区分内容。 If the

course is open to undergraduates, please indicate the difference.）

考核形式 Form of examination：本课采取期中考试和期末项⽬ PPT 展示的⽅式考核。

The form of examination will be mid-term exam and final presentation.

2. 分数构成 Grading policy

出席率/Attendance: 10%

期中考试/Mid-term exam: 40%

期末報告/Final presentation: 50%

14.

教材及其它参考资料

Textbook and Supplementary Readings

Textbook: Fundamentals of Neurodegeneration and Protein Misfolding Disorders

Author: Martin Beckerman

ISBN: 3-319-22117-5

Textbook: Molecular targets in protein misfolding and neurodegenerative disease

Author: Pierfausto Seneci

ISBN: 9780128001868

Scientific publications for reference:

1. Nature 2017 Jul 13;547(7662):185-190.

2. Nature 2020 Sep;585(7825):464-469.

3. Nature 2022 Mar 28. doi: 10.1038/s41586-022-04650-z.

4. Nature. 2022 Mar 28. doi: 10.1038/s41586-022-04670-9

5. Cell. 2022 Apr 14;185(8):1346-1355.e15.

6. Cell. 2022 Apr 14;185(8):1290-1292.