The term -synucleinopathies or also just synucleinopathies defines all members of a family of proteinopathies sharing as a common feature intracellular protein aggregates of aSyn51,52 in neuronal and/or glial cells. There are two major pathologies: on one hand Lewy-related -synuclein pathologies (LRP) comprising Lewy bodies and Lewy neurites and on the other hand glial cytoplasmatic inclusions (GCI)53,54. Lewy FH was the first to describe these inclusions in brain sections of PD patients in 1912 and Tretiakoff C later on in 1919 proved their presence in the substantia nigra55 naming these structures in Lewy’s honor. Another key finding is the presence of Lewy bodies in the cortex56. Pale bodies are considered precursors of Lewy bodies57.
Figure 1-4. Preliminary classification of synucleinopathies.
Preliminary classification of synucleinopathies and associated diseases using information provided by Alafuzoff et al.58 and McCann et al.59.
Lewy body composition has been in the focus of research over many years and fibrillar forms of aSyn have been identified as the key element often associated with post-translational modifications such as phosphorylation60, mainly residue S129, as well as high levels of aSyn ubiquitination61 and others. In fact anti-ubiquitin antibodies were used for Lewy body staining before knowing about aSyn’s role in synucleinopathies4. Importantly Lewy bodies are very diverse in their composition and should not be seen as pure inclusions of fibrillar synuclein. Indeed, more than 90 molecular components62 have been identified and some studies identified even more possible candidates (~400 proteins63), and similar findings have been reported for aSyn inclusions in animal
Introduction
model systems42. To the present day, it is not clear how LRPs and GCIs are associated with toxicity and cell death.
The best medical diagnosis of synucleinopathies still relies on the postmortem examination of defined brain areas using immunohistochemical techniques. Figure 1-4 shows the different diseases in a hierarchic chart.
Figure 1-5. Hallmark pathologic features of PD, DLB and MSA.
Parkinson’s disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA). NCI: neuronal cytoplasmatic inclusions, GCI: glial cytoplasmatic inclusions, SN:
substantia nigra. In green distinct pathologic features are indicated. Taken from McCann et al.59
Introduction
1.3.1 Parkinson’s disease
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder64 after Alzheimer’s disease (AD) affecting 950 individuals per 100,000 in the US65 which translates approximately in a prevalence rate of 1% in the Western world.
A European prevalence study suggests that by the year 2030 between 8.7 and 9.3 million people will be affected by PD66.
The main clinical criteria for PD diagnosis is the presence of two out of three motor signs: bradykinesia, rigidity and resting tremor67. In addition, non-motor symptoms such as sensory impairments, REM sleep disorders, depression, constipation, pain as well as cognitive deterioration can occur, often becoming noticeable before the onset of motor symptoms.
The mutations A30P68, E46K69, H50Q70, G51D71, A53T72 and A53E73 of aSyn are associated with familial forms of PD, as well as SNCA gene duplication74 and triplication75. Most of PD cases are sporadic. Key PD symptoms are directly linked to cell death of pigmented dopaminergic neurons in substantia nigra and are signs of dopamine deficiency. Post-mortem LPR in SN are detectable. Depigmentation of the substantia nigra can be readily observed in brain autopsy. Some PD patients also develop dementia and for some pathologists it is even classified as a distinct Lewy body disease, Parkinson’s disease with dementia (PDD) (Figure 1-4). LPRs do not differ much between PD, PDD and LBD. For correct assessment of the disease type, it is absolutely crucial that in case of PD and PDD, signs of dementia start after the advent of motor symptoms and vice versa of DLB59.
Besides symptomatic pharmacological therapy of PD76 by L-DOPA and surgical deep brain stimulation77, there is down to the present day no cure for the diseases . Thus, further fundamental research is required, in order to better understand and characterize the disease and eventually help the millions of people affected.
1.3.2 Dementia with Lewy bodies
Dementia with Lewy bodies overlaps closely in its pathology with PD. It follows Alzheimer’s disease as the most common form of dementia78. The worsening of cognitive functions associated with dementia has to precede motor symptoms for at least one year. LBP seems to be more pronounced in the cerebral cortex in comparison to PD (Figure 1-5).
Introduction
1.3.3 Multiple system atrophy
Multiple system atrophy (MSA) shows two disease subtypes. The first subtype named MSA-P is associated with classical symptoms also occurring in PD such as bradykinesia, tremor, rigidity and postural instability. The second subtype MSA-C affects mainly the cerebellum and the associated functions causing gait and speech problems as well as oculomotor dysfunctions79. MSA has a similar onset age as PD, but the survival time is much shorter with patients dying within 6-9 years.59 The most striking difference appears in the pathology, in MSA unlike any other synucleinopathy, the affected cells are non-neuronal oligodendrocytes of the brain glia and the hallmark feature are aSyn-positive glial cytoplasmatic inclusions (GCI) (Figure 1-5). Currently it is still an open question if the misfolded aSyn is expressed by the oligodendrocytes themselves80 or if there is a transmission pathway that allows transport of aSyn from neurons to glial cells81 and equally important what is the conformation of the aSyn species that occur in this neuron-to-glia transmission.
1.3.4 ADLB and others
Lewy body pathology has also been observed in a subpopulation of patients diagnosed with Alzheimer’s disease, specially within the amygdala82. These cases might represent a distinct pathologic entity or represent mixed-type pathologies of DLB and AD83, making it difficult to categorize unanimously. In addition, it is known that Lewy bodies occur in asymptomatic patients, which is referred to as “incidental Lewy bodies”
in the field. These cases could also represent preclinical stages of true synucleinopathies.