The document summarizes the relationship between autophagy pathways and Parkinson's disease. It finds that: 1) Failure of autophagy results in the accumulation of toxic protein aggregates in neurons, which can lead to neurodegeneration as seen in Parkinson's disease. Studies in mice and human cells support the role of impaired autophagy in Parkinson's pathology. 2) Several genes associated with Parkinson's disease are involved in autophagy regulation. Manipulating autophagy pathways has shown therapeutic potential in preclinical models of Parkinson's, though selectivity and context-dependence are challenges. 3) Personalized approaches may be needed, as autophagy enh

1. T.C
HACETTEPE UNIVERSITY
GRADUATE SCHOOL OF HEALTH SCIENCES
DEPAERMENT OF PHARMACOLOGY
Ahmed Algali Sedahmed ,
M.Sc student in pharmacology
Pharmacolgy department .
4/6/2021
Autophagy Pathways as Pharmacological Target in Parkinson's Disease

2. Autophagy Pathways as
Pharmacological Target in
Parkinson's Disease
The pathway holder of 2016 Nobel Prize in Physiology or Medicine

3. Seminar:
• What is Autophagy ?
• Is there is a relationship between the failure of Autophagy
and Parkinson's Disease (PD) ?
• Could the Manipulation of autophagy act as a possible
therapeutic approach in PD ?

4. What is Autophagy ?
• Auto-phagy = Self- eating
• Is a lysosomal degradation pathway that is essential for survival,
differentiation, development, and homeostasis.
• Types : 1.Macroautophagy “classic autophagy”
2.Microautophagy .
3.Chaperon-mediated autophagy.
• Degradation of substrates :
-proteins.
-lipid droplets.
-organelles.

5. Substrate proteins are delivered to lysosomes from the extracellular media
(heterophagy) or from inside the cell(autophagy).

6. Molecular Regulation of Autophagy
• Basal activity
• processes are triggered under conditions of cellular stress,
including starvation, oxidative stress and presence of protein
aggregates
• The mammalian target of rapamycin (mTOR), a 289-kDa
serine/threonine kinase, has been identified as a master
regulator of macroautophagy, that can be embedded in two
protein complexes: mTORC1 or mTOR2 mTOR –
dependent pathway.
• mTOR –independent pathway

7. Steps of Macroautophagy
Macroautophagy Autophagocytosis

10. The Failure of Autophagy Pathways

11. • Accumulation of toxic protein products or protein
aggregates has different consequences depending on the
cells affected.
Skin fibroblasts : aggregates distribute between mother
and daughter cells, acting as a diluting factor. However,
in postmitotic tissues (as the brain) , persistence of toxic protein
products inside cells results in cell death.
• Lost neurons cannot be replaced, and this progressive loss of neurons
eventually gives rise to symptoms. This disadvantageous
situation of neurons is the main reason why the more
detrimental protein conformational disorders are usually
those that affect the CNS.

13. Macroautophagy
• Conculsion (1) :
• It is very important mechanism of the cell that
removes unnecessary or dysfunctional components
especially neuronal cell.
• It has Complex , diverse ,shared ! regulatory
components in the pathways.

14. Is there is a relationship between the failure of
Autophagy and Parkinson's Disease (PD) ?
• What happens if neuronal autophagy is blocked ?

15. Hara et all 2006 nature
Histological examination revealed degenerative changes in the neurons
• Accumulation of inclusion bodies

16. Hara 2006 ,nature
• Demonstrated partial loss of neurons.
• Massive swelling of Purkinje cell axons that project to the
cerebellar nuclei.

17. • Mice deficient for Atg5 (autophagyrelated 5) specifically in
neural cells develop progressive deficits in motor function
that are accompanied by the accumulation of cytoplasmic
inclusion bodies in neurons.
• Rotarod and wire-hanging tasks also showed severely
impaired motor coordination, balance and grip strength in
Atg5 mice. Finally, tremor was apparent in 12-week-old mice.

18. D :Abnormal limb-clasping of an Atg5 flox/flox; nestin-Cre mouse compared with a control
mouse (Atg5 flox/þ; nestin-Cre) when suspended by its tail.
E:, Rotarod testing of Atg5 flox/þ; nestin-Cre (open symbols) and Atg5 flox/flox; nestin-Cre
(closed symbols) mice. One male and one female mouse were analysed for each genotype.
The time until drop from the rod (rotating at 20 r.p.m.) is shown.
Hara et all 2006 nature

19. Parkinson’s disease
• One of the pathological hallmarks of the
disorder is the presence of intracellular
inclusion bodies, Lewy bodies, that mainly
contain aggregated α-synuclein protein.
• Parkinson’s disease is characterised by
progressive and extensive loss of
dopaminergic neurons in the substantia nigra
pars compacta and the stratium.

21. ASHLEY RA, 2010

22. Genome-wide association studies
Moors et al ,2017

23. Postmortem studies of PD
• Postmortem studies demonstrated altered expression of
numerous ALP components in the PD brain compared to age-
matched controls:
o Decreased levels of lysosomal-associated membrane protein type 1 (LAMP1) in the
SN of PD patients.
o Deregulation of lysosomal enzymes, in particular Gcase, cathepsin A and cathepsin
D.
o Alterations for numerous autophagy-related processes, including mTOR signaling,
PI3K/AKT signaling and 14- 3-3 protein signaling, demonstrated by transcriptome
studies.
o Subcellular localization of TFEB was changed, as TFEB expression in the nuclear
department of dopaminergic neurons was significantly decreased.
Moors et al ,2017

25. J.
. D.Tourlerge et al 2016

26. Moors et al ,2017

27. • Conculsion (2) :
• Failure of Macroautophagy results in Portein aggregates + Neuronal cell
death= Neurodegeneration .
• Failure of this pathway contributes to the pathophysiology of
Parkinson's disease and manipulation of this failure may act as good
therapeutic strategy .

28. Drugs targeting the pathways
Key Regulators :
• Mammalian target of rapamycin1 (mTORC1)
• AMPK
Others :
• IMPase
• Calpains
• P13K class3

29. Drugs targeting the pathways

30. Stimulating macroautophagy in preclinical models of PD
Pilar Rivero-Ríos, 2016

33. Tim E. Moors et al ,2017

34. Macroautophagy: a double-edged sword :
• Upstream ALP signaling proteins are involved in many pathways other than autophagy - for
instance including apoptosis, cell growth, and immune responses.(Selectivity ?)
• Selective targeting of down stream ALP components
• Downstream of mTOR (TFEB)
• Direct targeting of lysosomes

36. Flash back point :
• Is every autophagy enhancing agent will be a
good candidate to treat every Parkinson’s
disease patient ?

37. Back to Macroautophagy

40. Personalized medicine – Parkinson disease ?

41. Clinical trails
• WHY ?

42. Conculsion (3) :
• Pharmacological autophagy enhancement ameliorated cell death and mitochondrial
dysfunction, possibly mediated by the increased clearance of damaged
mitochondria and increased α-syn clearance invitro and invivo model of PD.

43. Overall Conculsion
• Preclinical researches provided important knowledge about the role of
Autophagy in PD.
• The therapeutic potential of macroautophagy-enhancing agents may be
limited due lack of selectivity and the double-edged sword properties of
macroautophagy. compounds that selectively target downstream
components of the ALP, exert more specific effects and may have exciting
therapeutic perspective
• A better understanding of the role of ALP dysfunction in different genetic
and molecular subtypes of PD is essential for the design of future disease
modifying therapies. (Personalized Medicine ).

44. References
• Autophagy and neurodegeneration: when the cleaning crew goes on strike) Marta-
Vicente et al, Lancet Neurol (2007); 6: 352–61.
• Molecular changes in the postmortem parkinsonian brain, D.Tourlerge et al ,J.
Neurochem. (2016) 139 (Suppl. 1), 27--58
• Role of Autophagy in Parkinson’s Disease, Silvia Cerri et al , Current Medicinal
Chemistry, (2019), 26, 3702-3718.
• Suppression of basal autophagy in neural cells causes neurodegenerative disease
in mice , Taichi Hara, Nature (2006 ),Vol 441.
• -Synuclein impairs macroautophagy: implications for Parkinson’s disease, Ashley
R et al J. Cell Biol. (2010 ),Vol. 190 No. 6.
• Therapeutic potential of autophagy enhancing agents in Parkinson’s disease, Tim E.
Moors et al , Molecular Neurodegeneration (2017) 12:11 .
• Targeting the Autophagy/Lysosomal Degradation Pathway in Parkinson´s Disease,
Pilar Rivero-Ríos, Current Neuropharmacology, 2016, 14, 238-249.

45. ..THANK YOU..