Brief History of Parkinson's Disease

The motor symptoms of this pathology were first described in 1817 by James Parkinson. In his “Essay on the Shaking Palsy”, he reported the cases of 6 patients presenting with tremors at rest, bradykinesia and sometimes akinesia which led him to name the pathology “shaking palsy” (Kempster, Hurwitz, and Lees 2007). The first person to refer to this paralysis agitans as the PARKINSON’S DISEASE was William Rutherford Sanders in 1865 (Sanders 1865), then this designation was made famous in 1872 by the neurologist Jean‐Martin Charcot (Charcot 1872).

In 1895, Brissaud suggested that the substantia nigra pars compacta (SNpc) might be the affected area in PD (Brissaud 1895) after observing resting tremors resembling a parkinsonian syndrome in a patient with a tumor in the right cerebral peduncle that affected the ipsilateral SNpc (Blocq and Marinescu 1893).

In 1919, Trétiakoff was the first to observe a strong loss of neuromelanin in the SNpc of parkinsonian patients - due to the absence of neurons containing this pigment - as well as the presence cytoplasmic inclusions called Lewy bodies  (Trétiakoff 1919). He named them so because similar elements had previously been described in other brain regions of Parkinsonian patients by Fritz Jakob Heinrich Lewy in 1912 (Lewy 1912). He concludes that the tremors and rigidity of parkinsonian patients were caused by a degeneration of the SNpc.

In 1958, Carlsson identified the presence of dopamine (DA) in the brain and suggested that PD might be related to it (Carlsson 1959). DA deficiency in the striatum (ST) and SNpc of brains of parkinsonian patients was actually described in 1960 by Ehringer and Hornykiewicz (Ehringer and Hornykiewicz 1960). This discovery led to the development of therapeutic strategies aimed at increase dopaminergic transmission via the DA precursor, L‐3,4‐dihydroxyphenylalanine (L‐dopa).

The first link between PD, environment and mitochondria was made in 1983, when Langston and collaborators described the development of an acute parkinsonian syndrome in a group of drug addicts exposed to MPTP (1-methyl-4-phenyl-1,2, 3,6‐tetrahydropyridine), a mitochondrial toxin that inhibits complex I of the respiratory chain. Their syndrome was indistinguishable from PD (Langston et al., 1983). Subsequently, a marked decrease in the activity of complex I of the mitochondrial respiratory chain was described in the brains of Parkinsonian patients (Schapira 1993). The first hereditary forms of PD were identified in the late 1990s, with the discovery of mutations in the SNCA gene encoding the protein α-synuclein (αSyn) (Polymeropoulos et al. 1997). Then αsyn was identified as one of the main components of CL (Spillantini et al. 1997). In 2004, in some families, mutations in the gene encoding the protein Leucine‐Rich Repeat Kinase 2 (LRRK2) were identified (Paisán‐Ruíz et al. 2004; Zimprich et al. 2004). Then in 2005, 3 groups discovered the G2019S mutation in the kinase domain of this protein, which today is known to be the most common pathogenic variant of LRRK2-associated forms of PD (Di Fonzo et al. 2005; Hernandez et al. 2005; Kachergus et al. 2005).