Basic understanding of the autophagic mechanisms involved in CNS disorders

1. 1
AUTOPHAGY AND MITOPHAGY IN
NEURODEGENERATION
Presented by:
Singh Aditya Ajit
Department of Pharmacology and Toxicology
PC/2019/212
Guided by: Dr. Dharmendra Kumar Khatri

2. Contents
1. INTRODUCTION
2. MITOCHONDRIAAND PROTEIN QUALITY CONTROL IN NEURONS
3. AUTOPHAGY
4. MITOPHAGY
5. RECEPTORS INVOLVED
6. MITOPHAGYAND AUTOPHAGY IN NEURODEGENERATIVE DISEASES
7. MITOPHAGYAND AUTOPHAGY IN PARKINSON’S DISEASE(PD)
8. MITOPHAGYAND AUTOPHAGY IN ALZHEIMER’S DISEASE
9. FUTURE PERSPECTIVES IN MITOPHAGYAND AUTOPHAGY RESEARCH
10. REFERENCES
11. SUMMARY
2

3. What is
Neurodegeneration? Healthy
neuronal cells
Degenerative
processes
Cell
dysfunction
Cell death
Clinical signs
and symptoms
 It is the progressive loss of neurons
structure or functions
 Excess neurodegeneration may lead to
death of neurons
 It occurs as a result of many factors
including:
a) Protein misfolding
b) DNA damage
c) Mitochondrial dysfunction
3
Flow chart of Neurodegenerative process
Gitler AD, Dhillon P, Shorter J, Dis Model Mech. 2017;10(5):499–502.

4. Mitochondria and Protein Quality Control in
Neurons
 Due to metabolic features and
post mitotic state, neurons are
vulnerable to mitochondrial
dysfunction
 Besides cellular energy source,
mitochondria have important
functions such as:
i. Control of programmed cell
death
ii. Regulation of Ca+2 homeostasis
iii. Biosynthesis of protein co-
factors
4
Pfanner N, Warscheid B, Wiedemann N, Nat Rev Mol Cell Biol. 2019;20(5):267-284

5. Autophagy
 It is a self degenerative process
 It is a natural regulatory mechanism which retains beneficial substances and removes
harmful substances from body
 Plays role of housekeeping in removal of misfolded or aggregated proteins.
 It can be either selective or non-selective
 Stress and amino acid starvation are major reasons for autophagy.
5
Autophagy
Microautophagy Macroautophagy Chaperone
mediated
autophagy(CMA)
Mitophagy
Flow chart of Autophagy process
Wang Y, Liu N, Lu B, CNS Neurosci Ther. 2019;25(7):859–875.

6. Autophagic process and its pathways 6

7. Mitophagy
 Discovered by Lewis & Lewis
 A selective autophagic process to remove dysfunctional or damaged mitochondria
 To maintain normal mitochondrial turnover as well as cellular development and
differentiation
 Numerous studies in metazoans suggest the process to be regulated by PINK 1 and
Parkin
 In mammals mitophagy activated by:
i. Mitophagial receptors on outer mitochondrial membrane
ii. Ubiquitination
7
Palikaras K., Lionaki E. & Tavernarakis N, Nat Cell Biol .(2018);20(9):1013-1022

8. 8Mitophagy process

9. BNIP3 and
NIX/BNIP3L
FUNDC-1 mediated
BCL2L13 and FKBP8
Ambra1
9
PINK1/Parkin
mediated
LC3 adapters: p62
Mitophagy and Autophagy receptors in mammals Ubiquitin mediated interaction of LC3
adapters

10. Receptors Involved
 BNIP3 and BNIP3L: Regulated by hypoxia inducible factor (HIF) or forkhead homeobox type O
(FOXO)
 FUNDC1: Under hypoxia conditions, the FUNDC1 mRNA and protein levels are downregulated
attributable to mitophagy
 BCL2L13B and FKBP8: Bcl2-like 13 located on outer mitochondrial membrane (OMM) and can
bind to LC3 via the LIR motif, FK506- binding protein 8 is and LC3 interacting protein located on OMM
and can promote mitophagy in a Parkin dependent manner
 Ambra1: Ambra1 can transfer from cytoskeleton to ER and regulate autophagosome nucleation. Parkin
can interact with Ambra1,prolonged mitochondrial depolarization enhances interaction leading to
mitophagy
10
Youle R., Narendra D, Nat Rev Mol Cell Biol. (2011) ;12: 9–14

11. Ubiquitin Mediated Interaction of LC3
Adapters
 PINK1/Parkin mediated: These are most common pathogenic factor for recessive
familial Parkinson disease. PINK1 is a mitochondrial stress sensor whose function
depends on membrane potential
 LC3 adapters: These are autophagy adaptor proteins which posses the ubiquitin
binding domain and can interact with ubiquitinated mitochondrial proteins and the LIR
motifs for recruiting a separation membrane through interaction with LC3
11
Youle R, Narendra D, Nat Rev Mol Cell Biol. (2011) ;12: 9–14

12. MITOPHAGY AND AUTOPHAGY
IN NEURODEGENERATIVE
DISEASES
12

13. Mitophagy and Autophagy in Parkinson’s
Disease(PD)
 Parkinson’s disease affects the motor functions
 Symptoms are caused due to loss of dopaminergic neurons in the substantia nigra pars
compacta (SNpc) resulting in loss of dopamine(DA)
 Two genes PARK2 and PARK6 which encode Parkin and PINK1 respectively are
mutated
 Thus PINK1/Parkin mediated mitophagy is impaired
 Excess α-synuclein recruits miro protein and delays mitophagy
 Reduction of α- synuclein aggregation and induction of mitophagy by autophagy are
probable targets to alleviate PD
13
Vives-Bauza C, Przedborski S, Trends in Molecular Medicine.(2011);17(3): 158–165.

14. 14
Vives-Bauza, Przedborski S , Trends in Molecular Medicine.(2011);17(3): 158–165.
Parkin
PINK1
VDAC6
p62
Ubiquitinated
OMM
LC3-II
Autophagosome
A: Recruitment of cytosolic
Parkin by PINK1
B: Ubiquitination of OMM proteins
and recognition by p62
C: p62 binds to LC3-II of
Autophagosome
Mitophagial process that is impaired in PD

15. Mitophagy and Autophagy in Alzheimer’s
Disease
 This disease leads to loss of memory and cognitive functions
 Occurs as a result of accumulation of neurofibrillary tangles and extracellular senile
plaques containing amyloid β-peptide (Aβ)
 Mitochondrial biogenesis impaired due to low levels of PGC1-α
 The processes that contribute to neurodegeneration are:
a. Mitochondrial dysfunction
b. Oxidative stress and impairment of the autophagic system
15
Kerr JS, Adriaanse BA, Greig NH et al, Trends Neurosci. (2017);40(3):151–166.
Mitophagy and
Autophagy
stimulated
Lysosome Function
impaired
Autophagosome
fusion

16. Healthy neuron Damaged neuron in AD
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17. Future Perspectives in Mitophagy and
Autophagy Research
 Mitochondrial autophagy plays a huge role in self maintenance of neuronal system, but
only role of PINK1/Parkin have been extensively specified and other regulatory
systems are still under study
 Enhancement of lysosomal integrity to facilitate autophagic degradation of damaged
cellular constituents can be a potential therapeutic target
 Modulation of mitochondrial dynamics of PINK1/Parkin should be considered
 In a recent study, Nicotinamide treatment upregulated Mitophagy thus can be a
potential target for alleviating symptoms of Alzheimer’s disease.
17
Ashutosh Kumar et al ,CNS & Neurological Disorders - Drug Targets (2018);17: 696-703

18. Summary
 Mitophagy and autophagy are normal metabolic processes
 Effective regulation of these processes leads to recycling and maintenance of organelles
 An imbalance in the levels of mitophagy and autophagy leads to excess loss of cells and
can lead to neurodegeneration
 There is a genetic link between mitophagy and autophagy regulation as explained by
the disease pathogenesis
 These can be a potential target in upcoming development of drugs for symptomatic
treatment of neurodegenerative diseases.
18

19. References
 Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis
Model Mech. 2017;10(5):499–502
 Pfanner N, Warscheid B, Wiedemann N,Mitochondrial proteins:biogenesis to functional networks, Nat
Rev Mol Cell Biol. 2019;20(5):267-284
 Wang Y, Liu N, Lu B. Mechanisms and roles of autophagy in neurodegenerative diseases. CNS Neurosci
Ther. 2019;25(7):859–875
 Palikaras K, Lionaki & Tavernarakis, N,Mechanisms of mitophagy in cellular homeostasis, physiology
and pathology. Nat Cell Biol .(2018);20(9):1013-1022
 Youle R, Narendra D, Mechanisms of mitophagy,Nat Rev Mol Cell Biol. (2011) ;12: 9–14
 Vives-Bauza & Przedborski S. Mitophagy: the latest problem for Parkinson’s disease. Trends in
Molecular Medicine.(2011);17(3): 158–165
 Kerr JS, Adriaanse BA, Greig NH, et al. Mitophagy and Alzheimer's Disease: Cellular and Molecular
Mechanisms. Trends Neurosci. (2017);40(3):151–166
 Ashutosh Kumar et al Autophagy and Mitochondria: Targets in Neurodegenerative Disorders, CNS &
Neurological Disorders - Drug Targets (2018);17: 696-703
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