**2. Familial PD**

Familial PD is monogenic and caused by rare highly age-dependent penetrant mutations, which follow a Mendelial pattern of inheritance (autosomal dominant or recessive).

Fig. 1. The hyperbole descrives the relationship between the allelic frequency and the biological effect in the complex traits. The monogenic Mendelian forms are responsible for the familial Parkinson's disease, in which rare mutations can cause, independently from other factors, the disease, with a probability which increases with the age, due to the penetrance. The complex, poligenic, sporadic form is linked to risk factors which can be very common in the population but unable alone to determine the disease without interacting with other factors like genetic or environmental ones. Mutations in several familial (Mendelian) genes have been identified as causal factors for PD. Mutations in *LRRK2*, *SNCA*, *MAPT*, *UCHL1* determine the autosomal dominant disease while the recessive form is caused by mutations in *PARKIN*, *PINK1*, *DJ-1* and to a lesser extent *FBXO7* and *ATP 13A2*. Common variants in *SNCA*, *LRRK2*, *MAPT*, *HLA*, contribute to the development of the idiopatic disease. High-risk factors for the sporadic disease are mutations in *GBA* and *LRRK2* genes, especially among isolated populations like Ashkenazi Jews. Interestingly rare highly penetrant dominant mutations in *SNCA*, *LRRK2* and *MAPT* cause familial parkinsonian syndromes and common variants at the same loci increase susceptibility for PD in the general population.


16 Etiology and Pathophysiology of Parkinson's Disease

Familial PD is monogenic and caused by rare highly age-dependent penetrant mutations,

which follow a Mendelial pattern of inheritance (autosomal dominant or recessive).

Fig. 1. The hyperbole descrives the relationship between the allelic frequency and the biological effect in the complex traits. The monogenic Mendelian forms are responsible for the familial Parkinson's disease, in which rare mutations can cause, independently from other factors, the disease, with a probability which increases with the age, due to the penetrance. The complex, poligenic, sporadic form is linked to risk factors which can be very common in the population but unable alone to determine the disease without interacting with other factors like genetic or environmental ones. Mutations in several familial (Mendelian) genes have been identified as causal factors for PD. Mutations in *LRRK2*, *SNCA*, *MAPT*, *UCHL1* determine the autosomal dominant disease while the recessive form is caused by mutations in *PARKIN*, *PINK1*, *DJ-1* and to a lesser extent *FBXO7*

and *ATP 13A2*. Common variants in *SNCA*, *LRRK2*, *MAPT*, *HLA*, contribute to the development of the idiopatic disease. High-risk factors for the sporadic disease are

susceptibility for PD in the general population.

mutations in *GBA* and *LRRK2* genes, especially among isolated populations like Ashkenazi Jews. Interestingly rare highly penetrant dominant mutations in *SNCA*, *LRRK2* and *MAPT* cause familial parkinsonian syndromes and common variants at the same loci increase

**2. Familial PD** 


The classic approaches of linkage analysis and positional cloning have been very successful strategies to identify genes causing the autosomal-dominantly inherited diseases including

This strategy relies on the availability of large and clinically well-characterized families, usually with at least 8–10 affected family members. By studying the co-segregation of genetic (DNA)markers, the genetic locus of the disease-causing gene in a given family can be narrowed down to a region of several million base pairs (megabases, Mb) of DNA. The statistical method to estimate the likelihood that a particular set of neighbouring DNA markers (a so-called haplotype) are co-inherited with a disease gene as a result of its physical proximity on the chromosome (i.e. that DNA markers and disease gene are 'linked') is called linkage analysis. The most important prerequisite for this type of study, in addition to the availability of sufficiently large families, is the unequivocal classification of affected and unaffected family members. Erroneous classification, which in many age-related complex diseases is a real possibility, will lead to false linkage results (Gasser, 2008). When a disease locus is identified with sufficient confidence (a so-called lod score of >3 is equivalent to a genome-wide p.value of 0.05 and is considered to be significant evidence), all the genes in the identified region have to be sequenced and analysed for potentially disease-causing mutations. Of course, not all of the identified sequence variants in a linked region are pathogenic. This means that either the demonstration of mutations in several independent families co-segregating with a disease is necessary (amounting in effect to a replication of the initial finding) or the careful

functional studies in model systems are required to prove pathogenicity.

cells whereas α-synuclein is expressed in many areas of the brain.

can be an interesting target for the development of new therapies.

Mutations in the genes *LRRK2* and *SNCA* are responsible for the autosomal dominant form of the disease through a gain of toxic function. Mutations in *PARKIN*, *PINK1* and *DJ-1* are the most common cause of the autosomal recessive form through a loss of protective

It was the first gene to be inequivocally associated with familial autosomal dominant PD. It encodes for α-synuclein, a small protein, which is aboundantly expressed in the brain and localized mostly to presynaptic nerve terminals. This protein has a central role in the learning process, brain plasticity, vescicular trafficking and dopamine synthesis but many aspects of the normal function of alpha-synuclein are still unknown. There is still no good explanation for the selectivity of neural damage in PD, which is prominent in dopaminergic

Alpha synuclein plays a role in both familial and sporadic form of PD and for this reason

The protein is linked to the phospolipid membrane strate through the N-terminal edge and to a lesser extent it is free in the cytoplasm. It is hypothesized that a possible pathological role derives from a conformational change that lead to an imbalance between the protein linked to the membrane and that free in the cytoplasm, with a consequent aggregation and

Three missense mutations are causal factor for the familial autosomic dominant form of the

the major forms of familial PD.

function.

fibril formation.

disease

**3. Autosomal dominant PD 3.1 SNCA (PARK1 and 4, 4p21)**  The classic approaches of linkage analysis and positional cloning have been very successful strategies to identify genes causing the autosomal-dominantly inherited diseases including the major forms of familial PD.

This strategy relies on the availability of large and clinically well-characterized families, usually with at least 8–10 affected family members. By studying the co-segregation of genetic (DNA)markers, the genetic locus of the disease-causing gene in a given family can be narrowed down to a region of several million base pairs (megabases, Mb) of DNA. The statistical method to estimate the likelihood that a particular set of neighbouring DNA markers (a so-called haplotype) are co-inherited with a disease gene as a result of its physical proximity on the chromosome (i.e. that DNA markers and disease gene are 'linked') is called linkage analysis. The most important prerequisite for this type of study, in addition to the availability of sufficiently large families, is the unequivocal classification of affected and unaffected family members. Erroneous classification, which in many age-related complex diseases is a real possibility, will lead to false linkage results (Gasser, 2008). When a disease locus is identified with sufficient confidence (a so-called lod score of >3 is equivalent to a genome-wide p.value of 0.05 and is considered to be significant evidence), all the genes in the identified region have to be sequenced and analysed for potentially disease-causing mutations. Of course, not all of the identified sequence variants in a linked region are pathogenic. This means that either the demonstration of mutations in several independent families co-segregating with a disease is necessary (amounting in effect to a replication of the initial finding) or the careful functional studies in model systems are required to prove pathogenicity.

Mutations in the genes *LRRK2* and *SNCA* are responsible for the autosomal dominant form of the disease through a gain of toxic function. Mutations in *PARKIN*, *PINK1* and *DJ-1* are the most common cause of the autosomal recessive form through a loss of protective function.
