461:
206:
379:
259:). PINK1 is a protein normally transported into the mitochondrion, but can also accumulate on the surface of impaired mitochondria. Accumulated PINK1 then recruits Parkin; Parkin initiates the breakdown of dysfunctional mitochondria, a mechanism that acts as a "quality control". In Parkinson's disease, the genes coding PINK1 and Parkin are thought to be mutated so as to impair the ability of these proteins to breakdown dysfunctional mitochondria, leading to abnormal mitochondrial function and
233:
97:
323:
29:
346:. Microglia actively survey their environment and change their cell morphology significantly in response to neural injury. Acute inflammation in the brain is typically characterized by rapid activation of microglia. During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes the degradation of tissue and of the bloodâbrain barrier. During this time, microglia generate
492:, to motor neurons in the spinal cord. However, when a significant percentage of the motor neurons die (about 50-60%), this decreases dopamine levels by up to 80%. This inhibits the ability for neurons to generate and transmit a signal. This transmission inhibition ultimately causes the characteristic
274:
are highly reactive molecules that contain oxygen and can disrupt functions within the mitochondria and the rest of the cell. With increasing age, mitochondria lose their ability to remove ROS yet still maintain their production of ROS, causing an increase in net production of ROS and eventually cell
217:, is a mechanism by which inner components of the cell are broken down and recycled for use. Autophagy has been shown to play a role in brain health, helping to regulate cellular function. Disruption of the autophagy mechanism can lead to several different types of diseases like Parkinson's disease.
422:
are thought to be dysregulated in neurodegenerative diseases. The interaction between the VEGF protein and its receptors leads to cell proliferation, but is believed to be disrupted in
Parkinson's disease and Alzheimer's disease. This then causes cells to stop growing and therefore, prevents new
158:
This mechanism is substantiated by the facts that α-synuclein lacks toxicity when unable to form aggregates; that heat-shock proteins, which assist in refolding proteins susceptible to aggregation, beneficially affect PD when overexpressed; and that reagents which neutralize aggregated species
365:
factors. Microglia are usually in a resting state (M2), but in
Parkinson's disease can enter M1 due to the presence of α-synuclein aggregates. The M1 microglia release pro-inflammatory factors which can cause motor neurons to die. In this case, dying cells can release factors to increase the
120:(shown to left) in neurons. Traditionally, Lewy bodies were thought to be the main cause of cell death in Parkinson's disease; however, more recent studies suggest that Lewy bodies lead to other effects that cause cell death. Regardless, Lewy bodies are widely recognized as a
302:
appears to have a role in mediating separate pathological events that together ultimately result in cell death in PD. Oxidative stress leading to cell death may be the common denominator underlying multiple processes. Oxidative stress causes
447:
the brain. This mechanism is also known as vascular leakiness, where capillary degeneration leads to blood and blood proteins "leaking" into the brain. Vascular leakiness can eventually cause neurons to alter their function and shift towards
442:
in endothelial cells in the BBB help prevent large or harmful molecules from entering the brain by regulating the flow of nutrients to the brain. However, as gap junctions break down, plasma proteins are able to enter in
263:, and eventually cell death. Mitochondrial DNA (mtDNA) mutations have also been shown to accumulate with age indicating that susceptibility to this mechanism of neuronal death increases with age.
1461:
Nagasawa K, Chiba H, Fujita H, Kojima T, Saito T, Endo T, Sawada N (2006). "Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells".
334:, is generally understood for neurodegenerative diseases, however, specific mechanisms are not completely characterized for PD. One major cell type involved in neuroinflammation is the
1121:
Shimura-Miura H, Hattori N, Kang D, Miyako K, Nakabeppu Y, Mizuno Y (December 1999). "Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in
Parkinson's disease".
685:
Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK (Jul 2019).
438:
Without new capillary formation, the existing capillaries break down and cells start to dissociate from each other. This in turn leads to the breakdown of gap junctions.
68:
in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in
Parkinson's Disease include protein aggregation in
1335:"Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress"
415:
1411:"Differential effects of hydrocortisone and TNFα on tight junction proteins in an in vitro model of the human blood-brain barrier"
174:
1572:
402:. In neurodegenerative diseases, BBB breakdown has been measured and identified in specific regions of the brain, including the
1577:
244:
organelle. In
Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death.
1148:
Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K (April 2007). "Oxidative damage in nucleic acids and
Parkinson's disease".
1382:
Almodovar CR, Lambrechts D, Mazzone M, Carmeliet P (2009). "Role and
Therapeutic Potential of VEGF in the Nervous System".
460:
643:"DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms"
515:"Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention"
182:
104:
The first major proposed cause of neuronal death in
Parkinson's disease is the bundling, or oligomerization, of
1040:
Jomova K, Vondrakova D, Lawson M, Valko M (2010). "Metals, oxidative stress and neurodegenerative disorders".
803:
Hu Z, Yang B, Mo X, Xiao H (2014). "Mechanism and
Regulation of Autophagy and Its Role in Neuronal Diseases".
687:"Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders"
387:
85:
189:
reduces its nuclear levels leading to decreased DNA repair, increased DNA double-strand breaks and increased
411:
347:
271:
267:
247:
The mechanism behind mitochondrial dysfunction in
Parkinson's disease is hypothesized to be centered in the
485:
390:(BBB). The BBB has three cell types which tightly regulate the flow of molecules in and out of the brain:
343:
112:
has increased presence in the brains of Parkinson's Disease patients and, as α-synuclein is insoluble, it
58:
1002:
Lin MT, Beal MF (2006). "Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases".
283:
190:
170:
444:
339:
260:
378:
181:. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of
266:
Another mitochondrial-related mechanism for cell death in Parkinson's disease is the generation of
240:
The third major proposed cause of cell death in Parkinson's disease involves the energy-generating
113:
410:
in Alzheimer's disease. Protein aggregates or cytokines from neuroinflammation may interfere with
205:
28:
139:; patients at this stage are asymptomatic. As the disease progresses, Lewy bodies develop in the
839:"Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases"
431:. Cell receptor disruption can also affect the ability for cells to adhere to one another with
232:
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140:
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109:
96:
357:
are known to have two major states: M1, a state in which cells are activated and secrete
220:
Autophagy dysfunction in Parkinson's disease has also been shown to lead to dysregulated
1350:
1283:"Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders"
1516:
1489:
1435:
1410:
1359:
1334:
1307:
1282:
1222:
1197:
1098:
1071:
974:
948:"Parkin is recruited selectively to impaired mitochondria and promotes their autophagy"
947:
923:
896:
865:
838:
711:
686:
618:
593:
539:
514:
419:
128:
641:
Abugable AA, Morris JL, Palminha NM, Zaksauskaite R, Ray S, El-Khamisy SF (Sep 2019).
322:
1566:
770:
Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Ćos MJ (2014).
350:
and release signals to recruit peripheral immune cells for an inflammatory response.
304:
279:
788:
771:
481:
439:
428:
358:
241:
77:
255:
complex, having this been shown to drive autophagy of mitochondria (also known as
1426:
1263:
1246:
913:
659:
642:
609:
407:
391:
117:
1395:
1213:
897:"The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson's Disease"
702:
213:
The second major proposed mechanism for neuronal death in Parkinson's disease,
1088:
1053:
816:
578:
530:
330:
The fourth proposed major mechanism of neuronal death in Parkinson's Disease,
166:
185:. It was suggested that cytoplasmic aggregation of alpha-synuclein to form
449:
424:
399:
354:
335:
256:
221:
214:
186:
152:
148:
121:
73:
69:
65:
47:
1552:
1525:
1506:
1444:
1368:
1316:
1247:"The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders"
1231:
1179:
1134:
1107:
1023:
983:
932:
874:
720:
668:
627:
548:
57:
as a result of changes in biological activity in the brain with respect to
1409:
Förster C, Burek M, Romero IA, Weksler B, Couraud P, Drenckhahn D (2008).
964:
739:"Role for nanomaterial-autophagy interaction in neurodegenerative disease"
386:
The fifth proposed major mechanism for cell death is the breakdown of the
855:
473:
395:
291:
144:
51:
36:
A brain without and with Parkinson's Disease compared in Substantia Nigra
1015:
105:
1474:
1161:
755:
738:
565:
Schapira AH (2009). "Etiology and Pathogenesis of Parkinson Disease".
1170:
194:
178:
62:
54:
1298:
772:"Autophagy and apoptosis dysfunction in neurodegenerative disorders"
361:
factors; and M2, a state in which cells are deactivated and secrete
278:
As reviewed by Puspita et al. studies have demonstrated that in the
1072:"Oxidative stress and cellular pathologies in Parkinson's disease"
459:
377:
321:
248:
236:
A simplified illustration of energy production in a mitochondrion.
231:
204:
159:
protect neurons in cellular models of α-synuclein overexpression.
95:
468:
Dopaminergic neurons are the most abundant type of neuron in the
1539:
Barnett MW, Larkman PM, Larkman (2007). "The action potential".
488:. The activated motor neurons then transmit their signals, via
496:
with symptoms such as hunched and slowed walking or tremors.
472:, a part of the brain regulating motor control and learning.
1196:
Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010).
311:
of PD patients and may lead to nigral neuronal cell death.
382:
An image depicting bloodâbrain barrier shape and function.
1198:"Mechanisms Underlying Inflammation in Neurodegeneration"
169:
and Parkinsonâs disease. Alpha-synuclein activates ATM (
1488:
Marambaud P, Dreses-Werringloer U, Vingtdeux V (2009).
307:. Such damage is increased in the mitochondria of the
414:and alter their function in the BBB. Most notably,
21:
1456:
1454:
1276:
1274:
890:
888:
886:
884:
88:(BBB) breakdown resulting in vascular leakiness.
560:
558:
370:which causes continually increasing cell death.
61:(PD). There are several proposed mechanisms for
1065:
1063:
1035:
1033:
946:Narendra D, Tanaka A, Suen D, Youle RJ (2008).
326:Microglia(green) interacting with neurons(red).
1191:
1189:
1070:Puspita L, Chung SY, Shim JW (November 2017).
294:levels are likely involved in contributing to
732:
730:
680:
678:
8:
1328:
1326:
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993:
832:
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828:
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18:
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1087:
973:
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922:
912:
864:
854:
787:
754:
710:
658:
617:
538:
366:activation of M1 microglia, leading to a
165:appears to be a key link between reduced
1490:"Calcium signaling in neurodegeneration"
505:
44:pathophysiology of Parkinson's disease
464:An image depicting Parkinsonian gait.
7:
594:"α-Synuclein in Parkinson's disease"
1351:10.1016/j.freeradbiomed.2013.05.036
416:vascular endothelial growth factor
338:. Microglia are recognized as the
14:
1339:Free Radical Biology and Medicine
480:which modulates the activity of
209:An image illustrating Autophagy.
127:Lewy bodies first appear in the
100:A brain tissue with Lewy bodies.
76:, changes in cell metabolism or
27:
789:10.1016/j.pneurobio.2013.10.004
513:Tansey MG, Goldberg MS (2010).
124:marker of Parkinson's disease.
1463:Journal of Cellular Physiology
22:Neuronal Death in the PD brain
1:
737:Stern ST, Johnson DN (2008).
598:Cold Spring Harb Perspect Med
1427:10.1113/jphysiol.2007.146852
1264:10.1016/j.neuron.2008.01.003
914:10.1016/j.neuron.2014.12.007
895:Pickrell A, Youle R (2015).
660:10.1016/j.dnarep.2019.102669
952:The Journal of Cell Biology
610:10.1101/cshperspect.a009399
592:Stefanis, Leonidas (2012).
406:in Parkinson's disease and
1594:
1396:10.1152/physrev.00031.2008
1333:Hao T, Rockwell P (2013).
1214:10.1016/j.cell.2010.02.016
703:10.1038/s41598-019-47227-z
228:Changes in cell metabolism
183:non-homologous end joining
1415:The Journal of Physiology
1089:10.1186/s13041-017-0340-9
1054:10.1007/s11010-010-0563-x
817:10.1007/s12035-014-8921-4
579:10.1016/j.ncl.2009.04.004
531:10.1016/j.nbd.2009.11.004
35:
26:
843:Human Molecular Genetics
837:Chen H, Chan DC (2009).
776:Progress in Neurobiology
452:behavior or cell death.
298:as well as PD symptoms.
222:mitochondria degradation
519:Neurobiology of Disease
348:reactive oxygen species
268:reactive oxygen species
1507:10.1186/1750-1326-4-20
805:Molecular Neurobiology
486:central nervous system
465:
383:
368:positive feedback loop
344:central nervous system
327:
237:
210:
101:
1578:Programmed cell death
1384:Physiological Reviews
965:10.1083/jcb.200809125
463:
381:
325:
284:endoplasmic reticulum
235:
208:
191:programmed cell death
171:ataxia-telangiectasia
99:
1281:Zlokovic BV (2011).
1245:Zlokovic BV (2008).
456:Impact on locomotion
445:extracellular matrix
305:oxidative DNA damage
201:Autophagy disruption
1573:Parkinson's disease
1016:10.1038/nature05292
388:bloodâbrain barrier
340:innate immune cells
92:Protein aggregation
86:bloodâbrain barrier
59:Parkinson's disease
856:10.1093/hmg/ddp326
647:DNA Repair (Amst.)
567:Neurologic Clinics
466:
433:adherens junctions
384:
328:
238:
211:
173:mutated), a major
102:
1475:10.1002/jcp.20647
1162:10.1002/jnr.21191
1010:(7113): 787â795.
849:(R2): R169âR176.
756:10.4161/auto.7142
494:Parkinsonian gait
392:endothelial cells
363:anti-inflammatory
332:neuroinflammation
318:Neuroinflammation
177:repair signaling
137:pontine tegmentum
133:medulla oblongata
82:neuroinflammation
40:
39:
16:Medical condition
1585:
1557:
1556:
1536:
1530:
1529:
1519:
1509:
1494:Mol Neurodegener
1485:
1479:
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1458:
1449:
1448:
1438:
1421:(7): 1937â1949.
1406:
1400:
1399:
1379:
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1372:
1362:
1330:
1321:
1320:
1310:
1287:Nat Rev Neurosci
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1150:J. Neurosci. Res
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1042:Mol Cell Biochem
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943:
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936:
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916:
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834:
821:
820:
811:(3): 1190â1209.
800:
794:
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767:
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758:
749:(8): 1097â1100.
734:
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724:
714:
682:
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638:
632:
631:
621:
589:
583:
582:
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553:
552:
542:
510:
490:action potential
478:neurotransmitter
470:substantia nigra
404:substantia nigra
359:pro-inflammatory
309:substantia nigra
300:Oxidative stress
296:oxidative stress
141:substantia nigra
72:, disruption of
31:
19:
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1299:10.1038/nrn3114
1293:(12): 723â738.
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1239:
1195:
1194:
1187:
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1142:
1120:
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1048:(1â2): 91â104.
1039:
1038:
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288:alpha-synuclein
230:
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163:Alpha-synuclein
143:, areas of the
110:alpha-synuclein
94:
17:
12:
11:
5:
1591:
1589:
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1565:
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1480:
1469:(1): 123â132.
1450:
1401:
1390:(2): 607â648.
1374:
1322:
1270:
1257:(2): 178â201.
1237:
1208:(6): 918â934.
1185:
1140:
1113:
1059:
1029:
989:
958:(5): 795â803.
938:
907:(2): 257â273.
880:
822:
795:
762:
726:
674:
633:
604:(2): a009399.
584:
573:(3): 583â603.
554:
525:(3): 510â518.
504:
503:
501:
498:
457:
454:
427:formation via
420:VEGF receptors
412:cell receptors
375:
372:
319:
316:
229:
226:
202:
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129:olfactory bulb
108:. The protein
93:
90:
38:
37:
33:
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2:
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1203:
1199:
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1177:
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1163:
1159:
1156:(5): 919â34.
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482:motor neurons
479:
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440:Gap junctions
436:
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409:
405:
401:
397:
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389:
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374:BBB breakdown
373:
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353:In addition,
351:
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242:mitochondrion
234:
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200:
198:
196:
192:
188:
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180:
176:
172:
168:
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156:
154:
151:, and in the
150:
146:
142:
138:
134:
130:
125:
123:
119:
115:
111:
107:
98:
91:
89:
87:
83:
79:
78:mitochondrial
75:
71:
67:
64:
60:
56:
53:
49:
45:
34:
30:
25:
20:
1547:(3): 192â7.
1544:
1541:Pract Neurol
1540:
1534:
1497:
1493:
1483:
1466:
1462:
1418:
1414:
1404:
1387:
1383:
1377:
1342:
1338:
1290:
1286:
1254:
1250:
1240:
1205:
1201:
1153:
1149:
1143:
1129:(6): 920â4.
1126:
1122:
1116:
1079:
1075:
1045:
1041:
1007:
1003:
955:
951:
941:
904:
900:
846:
842:
808:
804:
798:
779:
775:
765:
746:
742:
697:(1): 10919.
694:
690:
650:
646:
636:
601:
597:
587:
570:
566:
522:
518:
508:
467:
437:
429:angiogenesis
385:
352:
329:
313:
280:mitochondria
277:
265:
246:
239:
219:
212:
161:
157:
126:
122:pathological
103:
52:dopaminergic
43:
41:
1345:: 421â431.
1123:Ann. Neurol
418:(VEGF) and
408:hippocampus
187:Lewy bodies
118:Lewy bodies
70:Lewy bodies
1567:Categories
653:: 102669.
500:References
400:astrocytes
261:morphology
175:DNA damage
167:DNA repair
147:and basal
114:aggregates
80:function,
1500:(1): 20.
1171:2324/8296
1082:(1): 53.
1076:Mol Brain
782:: 24â49.
743:Autophagy
450:apoptotic
425:capillary
396:pericytes
355:microglia
336:microglia
257:mitophagy
215:autophagy
153:neocortex
149:forebrain
74:autophagy
1553:17515599
1526:19419557
1445:18258663
1369:23732519
1317:22048062
1232:20303880
1180:17279544
1135:10589547
1108:29183391
1024:17051205
984:19029340
933:25611507
875:19808793
721:31358782
691:Sci. Rep
669:31331820
628:22355802
549:19913097
474:Dopamine
292:dopamine
282:and the
145:midbrain
116:to form
106:proteins
63:neuronal
1517:2689218
1436:2375735
1360:3756493
1308:4036520
1223:2873093
1099:5706368
975:2592826
924:4764997
866:2758711
712:6662836
619:3281589
540:2823829
484:in the
342:of the
275:death.
270:(ROS).
195:neurons
55:neurons
1551:
1524:
1514:
1443:
1433:
1367:
1357:
1315:
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1251:Neuron
1230:
1220:
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931:
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901:Neuron
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709:
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547:
537:
398:, and
253:Parkin
179:kinase
135:, and
84:, and
476:is a
249:PINK1
66:death
48:death
1549:PMID
1522:PMID
1441:PMID
1365:PMID
1313:PMID
1228:PMID
1202:Cell
1176:PMID
1131:PMID
1104:PMID
1020:PMID
980:PMID
929:PMID
871:PMID
717:PMID
665:PMID
624:PMID
545:PMID
290:and
251:and
42:The
1512:PMC
1502:doi
1471:doi
1467:208
1431:PMC
1423:doi
1419:586
1392:doi
1355:PMC
1347:doi
1303:PMC
1295:doi
1259:doi
1218:PMC
1210:doi
1206:140
1166:hdl
1158:doi
1094:PMC
1084:doi
1050:doi
1046:345
1012:doi
1008:443
970:PMC
960:doi
956:183
919:PMC
909:doi
861:PMC
851:doi
813:doi
784:doi
780:112
751:doi
707:PMC
699:doi
655:doi
614:PMC
606:doi
575:doi
535:PMC
527:doi
272:ROS
193:of
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