Destrucción de objetivos inmóviles

Lewy bodies contain mainly alpha-synuclein. However, a large number of different molecules have been identified within these inclusions. Some of these are proteins link to PD genes, such as DJ-1, LRRK2, Parkin and PINK1. Alongside these molecules, other protein constituents of Lewy bodies include are known to have roles in: mitochondrial function, the ubiquitin-proteasome system, aggresome formation and autophagy (Velayati et al., 2010; Wakabayashi et al., 2013).

49 The genes most commonly associated with familial PD are: Alpha-synuclein

(SNCA), Leucine Rich Kinase 2 (LRRK2), PTEN (phosphatase/tensin homolog on

chromosome 10)-induced putative kinase 1 (PINK1), Parkin and DJ-1 (Bonifati, 2014). The glucocerebrosidase gene (GBA1) encodes a lysosomal enzyme. Homozygous mutations of GBA1 are responsible for the metabolic disorder known as Gaucher disease (GD). It is now known that heterozygous mutations in this gene are one of the main risk factors for developing PD. GBA1 mutations have also been associated with DLB and MSA (Gámez-Valero et al., 2016; Mitsui et al., 2015). The neuropathology from people with PD and mutations in GBA1 is comparable to that of classical, sporadic PD (Aharon-Peretz et al., 2004; Ma et al., 2013; Sidransky et al., 2009). The main neuropathological features of individuals with mutations of these genes, is described in Table 2.1.

Gene Mutation/substitutions Neuropathological findings

SNCA

A53T

Severe neuronal loss in SN, LC and Widespread and diffuse LB, LN and thread like depositions, rarely GCI and tangles. Rarely, TDP-43-positive inclusions. Occasionally plaques A53T+S167N

PRKN polymorphism with AGD, FTLD. (Fujishiro et al., 2013;

Hoffman-Zacharska et al., 2013; Markopoulou et al., 2008) E46K Widespread LB pathology(Fujioka et al., 2014; Zarranz et al., ₂₀₀₄₎ A29S LB pathology(Fujioka et al., 2014)

G51D LB and tau pathology, TDP-53 pathology(Fujioka et al., 2014) A30P LB, LN, tau pathology and GCI (Fujioka et al., 2014; Seidel et al., ₂₀₁₀₎ H50Q LB, LN, tau pathology(Fujioka et al., 2014)

A18T NA (Hoffman-Zacharska et al., 2013)

A29S LB and LN pathology (Hoffman-Zacharska et al., 2013)

SNCA locus triplication Widespread LN, some GCI (Singleton et al., 2003b) and tangles _{(Fujishiro et al., 2013)}

SNCA locus duplication LB and tau pathology (Fujioka et al., 2014; Konno et al., 2016)

PINK1

N451S het Brainstem and neocortical LB in SN and neocortex. Diffuse Aβ _{deposits (Gandhi, 2006).}

Y431H het Severe neuronal loss in SN. LB in SN and neocortex. Sparse _{neurtic plaques (Gandhi, 2006)}

A339T het Severe neuronal loss in SN. LB in SN and neocortex. Diffuse Aβ _{deposits (Gandhi, 2006)}

C575R het Severe neuronal loss in SN. LB in SN and neocortex. Moderate _{neurtic plaques(Gandhi, 2006).}

50 PARKIN

R275W, del 40 bp Exon3 Neuronal loss in SN, LB in SN, LC, nBM, amygdala _{parahipocampal region (Farrer et al., 2001),} Hom del Ex 3 Moderate loss of neurons of SN and LC (Sasaki et al., 2004) delExon7, del1072T Severe neuronal loss in SN and LC, few LB in SN and LC (Mori et _{al., 2003)} Compound het Ex7

(C924T)

Neuronal loss in SN. LB in SN, LC and nbM (Schlossmacher et al., 2002)

Compound het (Ex7del+1072del)

SN, locus ceruleus, VNM and NA: Moderete - severe neuronal loss, reactive gliosis, neuritic dystrophy and LB. (Pramstaller et al., 2005)

Hom del Ex2+del Ex4 LB and LN in SN and LC, amygloid nucleus, VMN, nbM, striatum, _{anterior cingulate cortex. Tau positive inclusions in ETC} Compound het: acceptor

splice site mutation (IVS5- 1G>A) + Ex7del.

Severe neuronal loss in SN. ETC cortex with NFT and neruritis. Negative alpha-synuclein staining and LB no present.(Cornejo- Olivas et al., 2015; Pramstaller et al., 2005)

Compound het delEx3/del Ex4

Neuronal loss and presence of LB in SN and LC (Sharp et al., 2013)

Hom delEX3/del Ex 7 Severe neuronal loss in SN, less in LC. No LB and LN (Kitada et _{al., 1998)}

Hom delEx4 Severe neuronal loss in SN, less in LC. No LB and LN. Tau inclusions and NFT, thorn shaped astrocytes (Hayashi et al., 2000; Mori et al., 2003)

Compound het

delEx3/Ex6 transversion Severe neuronal loss in SN > LC. No LB and LN. Thorn shaped astrocytes (van de Warrenburg et al., 2001) Comp het delEx6/delEx7 Severe neuronal loss in SN > LC. No LB and LN .(Mori, 2003)

Hom delEx2 Severe neuronal loss in SN > LC. No LB and LN (Gouider-Khouja _{et al., 2003)}

Het C212Y PSP, neuronal loss in SN, striatum, GP, nbM, STN and Thalamus. _{No LB and LN. (Morales et al., 2002)}

Hom delEx3

Neuronal loss in SN and LC. No LB. Lewy-like inclusions in the anterior horn of the SC, asyn and ubiquitin positive (Sasaki et al., 2008)

LRRK2

G2019S

Severe-moderate neuronal loss in SN, LC and SI, ETC and VMN. LB in SN, LC, SI, amygdala, ETC, VMN, hypothalamus,

subthalamus, nbM, CG, medulla, BG, transentorhinal and FC. Tau-positive inclusions, aggregates of TDP-43 protein, ubiquitin- only inclusions as well as only dopaminergic neuronal loss without inclusions. Mild neuronal loss in SN. α-synuclein negaive LB and LN. (Dachsel et al., 2007; Gaig et al., 2007, 2008; Giasson et al., 2006; Gilks et al., 2005; Gomez and Ferrer, 2010; Rajput et al., 2006)

R1441C

Neuronal loss in SN and degeneration. Diffuse or brainstem LB pathology. Tau positive lesions with PSP-like pathology (Wider et al., 2010; Zimprich et al., 2004)

Y1699C Degeneration of SN. Ubiquitin positive inclusions in SN. Neuronal _{loss in SN and LC (Khan et al., 2005; Zimprich et al., 2004)}

R1441G Neuronal loss in SN and LC, no LB (Marti-Masso et al., 2009)

R1441R Neuronal loss in SN and LC (Craig, 2008)

I1371V Neuronal loss in SN and LC (Giordana et al., 2007)

R793M/L1165P Neuronal loss in SN and LC (Covy et al., 2009)

N1437H Neuronal loss in SN and LC, sparse NFT and Tau pathology _{(Puschmann et al., 2012)}

DJ-1

R98Q polymorphism LB and LN in SN (Bandopadhyay et al., 2004)

L172Q

Severe neuronal loss in SN, LC, GP and putamen. Diffuse LB pathology. Axonal a-syn positive spheroids and glial inclusions (Taipa et al., 2016).

51

RecNcil, RecA456P N370S hom; N370S het;

L444P/D409H+duplication Neuronal loss in SN. LB and LN in SN and CA2-4 hippocampus. (Tayebi et al., 2003)

N370S hom, N370S het, D409H/L444P+duplication

Neuronal loss with/without astrogliosis in SN, CA2-4, calcarine layer 4b and cortical layer 5. LB inclusions in SN and CA2-4. Gb- positive LB hippocampal inclusions. (Goker-Alpan et al., 2010; Wong et al., 2004)

N188S/E326K, T369M,

E326K, N370S, L444P Widespread extensive neocortical LB, AD-stages, PD or pure DLB (Gámez-Valero et al., 2016).

Table 2.1 Neuropathology findings in post-mortem brains with PD-related mutations. Amyloid-beta peptide

(Aβ), Alzheimer’s Disease (AD); Agyrophilic disease (AGD); alpha-synuclein (asyn); Dementia of Lewy bodies (DLB); Progressive supranuclear palsy (PSP); Frontotemporal lobar degeneration (FTLD); cingulate gyrus (CG); globus palidus (GP); sustantia nigra (SN); locus ceruleus (LC); entorhinal cortex (ETC); subthalamic nucleus (STN); glial cytoplasmic inclusions (GCI); Lewy bodies (LB); Lewy neurites (LN); motor nucleus of the vagus (VMN); basal nucleus of Meynert (nbM); nucleus ambiguous (NA); sustantia innominata (SI); neurofibrillary tangles (NFT); heterozygous (het), homozygous (hom); deletion (del); exon (Ex).